tokenpocket安全下载|erh

ehr 系统是什么？ erh 人力资源管理系统主要功能模块有哪些？ - 知乎

ehr 系统是什么？ erh 人力资源管理系统主要功能模块有哪些？ - 知乎首页知乎知学堂发现等你来答​切换模式登录/注册人力资源（HR）人力资源管理eHRehr 系统是什么？ erh 人力资源管理系统主要功能模块有哪些？关注者6被浏览3,170关注问题​写回答​邀请回答​好问题​添加评论​分享​4 个回答默认排序欢雀HRSaaS​ 关注ehr 系统是什么？EHR人力资源管理系统主要在人力资源规划、招聘与配置、培训与开发、绩效管理、薪酬福利管理、员工关系管理等板块中发挥着重要的作用。帮助企业对人力资源进行信息化、流程化、规范化管理提供了重要保障。在没系统辅助的情况下，单纯靠HR去管理，是很难帮助企业管理好员工和提高效率的，特别是企业规模越来越大的情况下。咱们欢雀HR SaaS深耕于人力资源服务领域，为企业级客户提供专业的人力资源管理系统，以提升企业管理水平为目标，欢雀HR人事软件涵盖集团管理、组织人事、招聘管理、绩效管理、薪酬管理、流程审批、培训管理、人才发展等多个模块，打通企业管理各个环节，以SaaS等方式实现信息共享，打破人力资源管理壁垒；以移动互联技术连接企业与员工，全员参与管理，企业赋能于员工，员工聚能于企业，达到企业管理的快速高效。有兴趣的可以来注册体验一下欢雀HR的人力资源管理系统：简单介绍下咱们欢雀HR人事系统各模块的功能1、招聘管理模块招聘管理拥有一站式招聘管理，自动归集并智能解析多渠道简历；自动生成企业专属人才库存储，信息永久留存；招聘计划、面试到Offer全流程无纸化管理；招聘数据分析，实时生成各维度透视报表。招聘管理2、考勤管理模块考勤管理拥有丰富的打卡方式：支持WIFI，GPS定位考勤，同时支持考勤机云绑定（指纹、刷卡、人脸识别均可），智能识别打卡方式，精确展示员工的每一次打卡信息；强大的考勤规则设置，坐班排班轻松管理，支持多规则考勤、精细排班、调班、特殊日期设置、加班调休等考勤设置，考勤排班从未如此简单；支持按规则自动生成年假额度，智能分配调休假，以及假期申请的条件限制等规则设置。轻松管理员工假期账户；完整记录员工的每一次打卡信息，自动判断考勤异常，自动统计考勤数据，支持数据导入导出，发送员工考勤数据确认，并可关联薪酬核算。考勤管理3、薪酬管理模块强大的薪酬规则设置，支持多账套设置，自定义薪酬结构，内置灵活的薪酬计算公式，无需学习软件代码即可快速上手；线下专业团队提供全国300+城市的社保数据自动更新。支持最新个税专项附加扣除计算、劳务个税计算等，让你算薪更准确；自动关联考勤扣罚、津贴补助、社保数据及个税核算，一键自动算薪；薪酬全盘数据展示及分类展示（薪酬表、社保表、公积金表、个税表、银行表等）。支持导入导出，更支持电子工资条发放，从此告别纸质工资条。薪酬管理4、绩效管理模块绩效管理支持360、KPI等多种考核工具；支持自定义考核方案、规则、指标、周期及评估流程绩效管理全面把控。绩效管理5、培训管理模块基于人才盘点结果，分析学习内容/形式，确定学习过程，输出学习路径图，帮助课程实施与现场管理，推进学习计划执行；从现场满意、学习过程、行为改变、绩效提升四个维度进行学习效果评价，输出培训效果报告；基于学习资源、学习项目和学习行为等基础数据，智能分析出各种数据结论，为培训管理监控、运营、决策提供依据。培训管理6、人才测评模块人才测评模块能构建企业核心岗位专属人才标准，同时亦可结合企业战略和人员绩效变化完成人才标准的敏捷迭代；依据人才标准，选择大五性格、职业潜能、心理健康等合适的评价工具，完成评价，并沉淀成人才档案，让人员的入、转、调、离有据可依；分析人才评价相关数据，多维度绘制企业内部人才地图，帮助业务管理者和HR清晰内部人才梯队，并做出人事决策。人才测评7、员工管理模块员工花名册全面记录员工信息，支持批量导入导出、批量更新，存档备份，支持自定义字段设置及自定义表头展示。更有员工轨迹记录，精准记录员工在职生涯成长印记；员工异动统一管理：入职、转岗、调岗、晋升、离职一键操作。关键时间节点消息提醒，是你最贴心的风险管控专家；一键上传员工所有纸质档案，数十种员工常用文档随需下载，支持员工档案关键信息统计及导入导出，员工还可自助扫描上传文件，彻底释放您的双手。员工管理8、决策分析模块该模块能多维度人力数据统计，有多达59个维度的人力数据实时统计，全面覆盖企业人事管理的人员信息，考勤数据及薪酬；支持多维度时间及组织范围数据统计分析，可实现数据穿透，更支持自定义人事报表统计分析，让你的人事管理工作游刃有余+城市的社保数据自动更新。支持最新个税专项附加扣除计算、劳务个税计算等，让你算薪更准确。决策分析9、组织管理模块支持集团化组织架构管理，组织架构备份及时间切片，拖拽式组织架构变更及架构自动生成，更支持虚拟组织管理，让你及时跟上快速变化的时代，满足高速变化的市场需要。有些模块可能没有写出来，但市面上大多数人力资源管理系统基本都是这些模块了，个别还会有定制化的需求，这个是需要根据企业的需求开发的，基本上都能支持。组织管理企业整体人力资源管理的水平得到了很大的提高，树立了自己的良好的形象，形象了良好的社会效益。 欢雀科技将会持续为大家提供人力资源行业资讯和相关问题解答，同时我们开发的欢雀HR SaaS人力资源管理系统已得到了国内数千家企业的选用和认可，帮助企业实现了考勤管理、智能排班、薪资绩效、电子签约等方面的信息化管控和数据分析，提高了企业的管理效率，降低了人力资源成本。发布于 2022-11-17 16:22​赞同​​添加评论​分享​收藏​喜欢收起​myDHR亚派 陈锦森​HR数字化转型，三支柱思想，帮助HR更好服务员工​ ​ 关注从功能视野了解目前的场景：1、人员招聘管理 制定岗位需求信息，执行招聘广告，向社会或校园募集有才人士。工作人员被录用以后，要有一定的试用期。试用期满后，根据考察结果，对符合条件的予以正式任用。2、员工的晋升、调动或调整 做好各岗位的职责说明，并根据企业职位需求，或为达到在职训练的目的，或为调整“人与人”、“人与事”的关系，采取调动工作人员工作岗位的措施。3、续签、终止劳动合同关系的管理 对实习到期符合企业岗位需求的人员进行续签，对不合格岗位需求的进行终止合同关系，只有任免得当，才能人尽其才，否则将会贻误工作。4、考勤管理 对企业员工上下班、请假、加班、调休进行管理。5、福利待遇 拟定薪酬制度及考核制度。6、员工培训 对新员工入职进行培训或者针对员工进行职能竞岗培训。7、绩效考核 通过考核，全面了解工作人员的优劣短长，可以为识别、使用、培训、调动、奖惩工作人员，以及实行按劳分配原则提供可靠的依据，也是激励先进、鞭策后进、巩固岗位责任制的重要措施。换一个视野，从人力资源管理六大模块1、人力资源规划 规划是明确目标、理清现状、制定方针政策和计划的过程；是企业为了实现发展目标，对人力资源的需求和供给进行预测，并努力使之平衡的过程。2、人才招聘与配置 根据岗位需求，科学合理地吸引、甄选、录用人才，并在合适的时间里将合适的人配置到合适岗位上，安排其合适的工作任务。3、员工培训与开发 企业管理的关键就是人的管理，人的管理关键是不断挖掘人的潜能，使人力资源变为人力资本，并不断使人力资本升值，通过培训来实现潜能的开发至关重要。4、绩效管理 企业组织通过对部门或员工的工作结果、行为表现、工作态度以及综合素质的全面监测、分析和评价，不断改善员工行为，提高素质，挖掘潜力，从而实现企业战略目标。5、薪酬管理 经济学角度给薪酬的定义是：劳动者在市场中创造价值的价格。这个价值需要通过岗位调查、岗位分析、岗位评价获得；这个价格的管理就如同商品的价格管理一样，需要策略。6、劳动关系管理 以法律为准绳，以道德为界限，极力营造和谐的劳动关系。编辑于 2022-12-28 15:30​赞同​​添加评论​分享​收藏​喜欢收起​​

ERH 因艾希｜抗污染、零傷害，適合所有肌膚的綠色科技保養品

ERH 因艾希｜抗污染、零傷害，適合所有肌膚的綠色科技保養品

{{ 'fb_in_app_browser_popup.desc' | translate }}

{{ 'fb_in_app_browser_popup.copy_link' | translate }}

{{ 'close' | translate }}

{{ 'in_app_browser_popup.desc' | translate }}

{{ 'close' | translate }}

{{word('consent_title')}}

{{word('consent_desc')}} {{word('read_more')}}

{{word('settings')}}

{{word('accept')}}

{{word('consent_title')}}

{{word('consent_desc')}} {{word('read_more')}}

{{setting.title}}

{{setting.description}}

{{word('save_preferences')}}

通過歐洲COMPLIFE人體臨床實驗證實，ERH粉刺水減少粉刺數量11.7%，減少痘疤黑色素沉澱11.4%，效果看得見

【AA級輕電波保養】雙A醇精華液擊退初老紋、緊緻提拉，成就無齡肌

通過歐洲COMPLIFE人體臨床實驗證實，ERH粉刺水減少粉刺數量11.7%，減少痘疤黑色素沉澱11.4%，效果看得見

【AA級輕電波保養】雙A醇精華液擊退初老紋、緊緻提拉，成就無齡肌

通過歐洲COMPLIFE人體臨床實驗證實，ERH粉刺水減少粉刺數量11.7%，減少痘疤黑色素沉澱11.4%，效果看得見

繁體中文

English

繁體中文

找商品

最新消息

年前倒數衝刺保養專區

因艾希粉會員優惠攻略

全部商品

產品類別

卸妝/潔顏

化妝水

精華液/精華油

乳液/乳霜

面膜

身體保養

眼唇保養

隔離防曬

肌膚問題及需求

乾燥脫皮

美白淡斑

黑頭粉刺

緊緻毛孔

抗老緊緻

敏感泛紅

皮膚粗糙

保濕修護

膚色暗沉

依功能找產品

保濕

美白

粉刺/抗痘/控油

緊緻

舒緩修護

煥膚

防曬

眼周護理

沐浴&身體

依成分找產品

杏仁酸 Mandelic Acid

富勒烯 Fullerene

神經醯胺/賽洛美 Ceramide

維他命B5 Vitamin B5

A醇 Retinol

補骨脂酚 Bakuchiol

藍銅胜肽 Copper Peptide

玻尿酸Sodium Hyaluronate

鎖水磁石 Pentavitin®

鳳梨釋迦萃取 AnnonaSense CLR™

關於ERH

品牌故事

綠色工廠

ERH專欄

購物車

你的購物車是空的

{{ 'product.bundled_products.label' | translate }}

{{ 'product.bundle_group_products.label' | translate }}

{{ 'product.buyandget.label' | translate }}

{{ 'product.gift.label' | translate }}

{{ 'product.addon_products.label' | translate }}

{{item.product.title_translations|translateModel}}

{{ field.name_translations | translateModel }}

{{ childProduct.title_translations | translateModel }}

{{ getChildVariationShorthand(childProduct.child_variation) }}

{{ getSelectedItemDetail(selectedChildProduct, item).childProductName }}

x {{ selectedChildProduct.quantity || 1 }}

{{ getSelectedItemDetail(selectedChildProduct, item).childVariationName }}

{{item.variation.name}}

{{item.quantity}}x

NT$0

{{ item.unit_point }} 點

刪除

{{ 'product.addon_products.label' | translate }}

{{addonItem.product.title_translations|translateModel}}

{{addonItem.quantity}}x

{{ mainConfig.merchantData.base_currency.alternate_symbol + "0" }}

刪除

{{ 'cart.checkout' | translate }}

你的購物車是空的

{{ 'product.bundled_products.label' | translate }}

{{ 'product.bundle_group_products.label' | translate }}

{{ 'product.buyandget.label' | translate }}

{{ 'product.gift.label' | translate }}

{{ 'product.addon_products.label' | translate }}

{{item.product.title_translations|translateModel}}

{{ field.name_translations | translateModel }}

{{ childProduct.title_translations | translateModel }}

{{ getChildVariationShorthand(childProduct.child_variation) }}

{{ getSelectedItemDetail(selectedChildProduct, item).childProductName }}

x {{ selectedChildProduct.quantity || 1 }}

{{ getSelectedItemDetail(selectedChildProduct, item).childVariationName }}

{{item.variation.name}}

{{item.quantity}}x

NT$0

{{ item.unit_point }} 點

刪除

{{ 'product.addon_products.label' | translate }}

{{addonItem.product.title_translations|translateModel}}

{{addonItem.quantity}}x

{{ mainConfig.merchantData.base_currency.alternate_symbol + "0" }}

刪除

{{ 'cart.checkout' | translate }}

目錄 最新消息 年前倒數衝刺保養專區 因艾希粉會員優惠攻略 全部商品 產品類別 卸妝/潔顏 化妝水 精華液/精華油 乳液/乳霜 面膜 身體保養 眼唇保養 隔離防曬 肌膚問題及需求 乾燥脫皮 美白淡斑 黑頭粉刺 緊緻毛孔 抗老緊緻 敏感泛紅 皮膚粗糙 保濕修護 膚色暗沉 依功能找產品 保濕 美白 粉刺/抗痘/控油 緊緻 舒緩修護 煥膚 防曬 眼周護理 沐浴&身體 依成分找產品 杏仁酸 Mandelic Acid 富勒烯 Fullerene 神經醯胺/賽洛美 Ceramide 維他命B5 Vitamin B5 A醇 Retinol 補骨脂酚 Bakuchiol 藍銅胜肽 Copper Peptide 玻尿酸Sodium Hyaluronate 鎖水磁石 Pentavitin® 鳳梨釋迦萃取 AnnonaSense CLR™ 關於ERH 品牌故事 綠色工廠 ERH專欄 分類 最新消息 年前倒數衝刺保養專區 精選商品 全部商品 產品類別 卸妝/潔顏 化妝水 精華液/精華油 乳液/乳霜 面膜 眼唇保養 身體保養 隔離防曬 肌膚問題及需求 乾燥脫皮 美白淡斑 黑頭粉刺 緊緻毛孔 抗老緊緻 敏感泛紅 皮膚粗糙 保濕修護 膚色暗沉 依功能找產品 保濕 美白 粉刺/抗痘/控油 緊緻 舒緩修護 煥膚 防曬 眼周護理 沐浴&身體 依成分找產品 杏仁酸 Mandelic Acid 富勒烯 Fullerene 神經醯胺/賽洛美 Ceramide 維他命B5 Vitamin B5 補骨脂酚 Bakuchiol A醇 Retinol 藍銅胜肽 Copper Peptide 玻尿酸Sodium Hyaluronate 鎖水磁石 Pentavitin® 鳳梨釋迦萃取 AnnonaSense CLR™ 帳戶 會員登入 新用戶註冊 其他 聯絡我們 繁體中文 語言 English 繁體中文 貨幣 $ HKD P MOP ¥ CNY $ TWD $ USD $ SGD € EUR $ AUD £ GBP ₱ PHP RM MYR ฿ THB د.إ AED ¥ JPY $ BND ₩ KRW Rp IDR ₫ VND $ CAD

加入購物車 加入購物車

香氛緊緻纖體油 Tonic Treatment Oil NT$980

回購率No.1

加入購物車 加入購物車

20%杏仁酸煥膚美白精華液 Mandelic Acid All-In-One Solution NT$750

超人氣新品

加入購物車 加入購物車

雙A醇‧新生彈力精華液1.5% Retinol+1.5% Bakuchiol Solution NT$880

精華油入門首選

加入購物車 加入購物車

滴精萃‧滿分賦活油100% Pure Plant Oil NT$500 ~ NT$1,180

加入購物車 加入購物車

絕對完美熬夜霜 Premium 24hr Youth Renewing Cream NT$500 ~ NT$2,000

粉刺救星

加入購物車 加入購物車

淨膚粉刺調理水 Ultra Reset Exfoliating Treatment NT$1,180

敏感肌推薦

加入購物車 加入購物車

AI‧舒醒健康精華液 AI-Replenishing Microbiome Essence NT$500 ~ NT$1,180

熱銷30萬瓶

加入購物車 加入購物車

絕對修護保濕精華油 Intensive Ceramide Oil Emulsion NT$500 ~ NT$1,500

加入購物車 加入購物車

白夏菊淨膚卸妝露 Makeup Remover Lotion (Chamomile Oil Free Cleansing Lotion) NT$400 ~ NT$980

加入購物車 加入購物車

25%胺基酸柔敏潔顏慕絲Cleansing Mousse with 25% Amino Acid for Sensitive Skin NT$350

售完 透皙明亮潔膚乳Facial Cleanser NT$350 ~ NT$990

加入購物車 加入購物車

透皙植物深層卸妝乳Make-Up Remover NT$480 ~ NT$890

體現十年磨一劍的氣概!利用高科技萃取技術、獨家配方、醫學背景研發團隊、最環保的ECOCERT有機工十年磨一劍的氣概!利用高科技萃取技術、獨家配方、醫學背景研發團隊、最環保的ECOCERT有機工廠製程以及最嚴格龜毛的創辦人。等等元素連成一氣，致力於研發快速有效及對環境友善的保養品，用最純淨天然的保養品，細心呵護現代人的肌膚

 

近期文章

A醇功效、A醇使用方法完整解答，你用對了嗎?

熬夜皮膚變差！專家傳授4招熬夜保養秘訣，擊退熬夜倦容

「維生素C」可以美白抗老？關於維他命C功效的全方位保養指南

神經醯胺（Ceramide）功效、有副作用？五大重點一次解析

 

更多ERH肌膚專欄 >

關於我們

品牌故事綠色工廠會員招募

 

姐妹品牌

膜殿 Maskingdom

Babysassi

顧客服務

運送服務方式購物須知退換貨政策條款與細則

聯絡我們

電話 / +886-2-26270028傳真 / +886-2-7721-0778marketing@10art.com.tw

獲得最新消息！

訂閱我們的精選內容，獲得第一手活動訊息。

訂閱

$ HKD

P MOP

¥ CNY

$ TWD

$ USD

$ SGD

€ EUR

$ AUD

£ GBP

₱ PHP

RM MYR

฿ THB

د.إ AED

¥ JPY

$ BND

₩ KRW

Rp IDR

₫ VND

$ CAD

繁體中文

English

繁體中文

Powered by SHOPLINE

[Q&A]NSX断路器�数ERH和RH是什么��？ | 施�德电气 China

[Q&A]NSX断路器�数ERH和RH是什么��？ | 施�德电气 China

{}

跳至主�内容

China

我们的�牌

购物车中的产�数�为

0

我的产�

购物车中的产�数�为

0

文档收�

我�注册

User name

我们的�牌

0

文档的数�为

Cancel

产�

�务

解决方案

�享�质家居

支�

公�信��招�

China

我们的�牌

我的产�

购物车中的产�数�为

0

文档收�

购物车中的产�数�为

0

我�注册

User name

欢�访问施�德电气网站

欢�访问我们的网站。

留在此网站

选择您的所在地

支��索常�问题FA411851

�索常�问题解答 �索

[Q&A]NSX断路器�数ERH和RH是什么��？问题�述：NSX断路器�数ERH和RH是什么��？所�产�线：Compact NSX解决方法：RH：直�旋转手柄 ERH：延伸旋转手柄首次�布日期:8/23/2020修订日期:8/24/2020是�有帮助？是� �索更多范围：ComPacT NSX

�索更多范围：ComPacT NSX

需�帮助？

�此处开始�

立�找到答案。自行�索解决方案，或者�系我们的专家。

��支�

我们的客户关爱团队�为您�供详细信��技术支��投诉帮助等�务，请�系他们。

�览常�问题解答

通过�览�主题相关的常�问题解答 (FAQ)，��您需�的答案。

我�采购

开始在线采购咨询，专家将会�您�系�

�收订阅的电�邮件地�：

�刻�收件箱中收到施�德电气的�月更新。

我��通过电�邮件�短信�电�等方��收施�德电气�其关�公�的产�新闻和商业广告信�,并��收集邮件打开和点击信�以衡�和改善通信性能。

商业�销数��护���声�。

电�邮件

请输入有效的电�邮件地�

我是一�...

我是一�...

零售商/门店

总包商

设计院

电气分销商

家装/工装电工

IT渠��作伙伴

机器制造商/OEM

�套�/盘�

�务�软件�供商

建筑系统集�商

工业系统集�商

电力系统集�商

中���业(<1000人)

大��业(>1000人)

房屋建筑商/开�商

消费者/个人

学生/求�者

订阅

快速链�

所有产�

解决方案

软件

+全生命周期�务

�作伙伴

EcoStruxure���平�

客户�功案例

è�Œä½�æ�œç´¢  opens in new Window

å�šå®¢  opens in new Window

关�我们

公�介�

人�招���业�展

��续�展

多元化

数���和Cookie政策

�访问性

�务

�场�务

数字化�务

咨询和培训

软件

工业自动化软件

数�中心软件

支�

需�帮助？点击此处开始

产�选�工具

产�文档和软件下载

�览常�问题解答

Green Premium产�

�系我们

�系中心

��支�

è�·å�–报价  opens in new Window

销售网点

查找施è€�德电气åŠ�事处  opens in new Window

查找培训中心  opens in new Window

解决方案

自动化�电动出行

云计算和�务供应商

商业建筑

数�中心

食��饮料

医疗

酒店

生命科学

机械

海事

矿业�采矿�冶金

电机管�

电力电网

交通

水务���公用事业

支�中心热线 4008101315

使用�款

京ICP备05053940å�·-6  opens in new Window

更改您的 cookies 设置

 opens in new Window

©2024, Schneider Electric

感谢您的订阅

�在，您将是第一个了解施�德电气最新动�的用户。您很快将收到欢��。希望您会喜欢�

访问模�关闭

访问模�开�

百度知道 - 信息提示

百度知道 - 信息提示

百度首页

商城

注册

登录

网页

资讯

视频

图片

知道

文库

贴吧采购

地图更多

搜索答案

我要提问

百度知道>提示信息

知道宝贝找不到问题了>_

该问题可能已经失效。返回首页

15秒以后自动返回

帮助

 | 意见反馈

 | 投诉举报

京ICP证030173号-1   京网文【2023】1034-029号     ©2024Baidu  使用百度前必读 | 知道协议 

Just a moment...

a moment...Enable JavaScript and cookies to continue

erh是什么意思_erh的翻译_音标_读音_用法_例句_爱词霸在线词典

什么意思_erh的翻译_音标_读音_用法_例句_爱词霸在线词典首页翻译背单词写作校对词霸下载用户反馈专栏平台登录erh是什么意思_erh用英语怎么说_erh的翻译_erh翻译成_erh的中文意思_erh怎么读,erh的读音,erh的用法,erh的例句翻译人工翻译试试人工翻译翻译全文erh英 ['əh]美 ['əh]释义[医][=egg-laying release hormone]排卵释放激素大小写变形:ErhERH点击 人工翻译，了解更多 人工释义实用场景例句全部Wan - erh's anger mounted , but there was misery in her voice.婉儿更气了, 声音里充满了苦恼.汉英文学 - 家（1-26） - 家（1-26）Wan - erh asked Ming - feng softly. She spoke more slowly than usual.婉儿用更低的声音问 鸣凤 道,声音很温和,比她平时说话慢了些.汉英文学 - 家（1-26） - 家（1-26）Hai - erh is very intelligent . He's obedient too . We all like him.海儿很聪明,又肯听大人的话,我们都喜欢他.汉英文学 - 家（1-26） - 家（1-26）Once in a while , Hsi - erh or Chien - erh came to see her.有时候婉儿 、 倩儿 或喜儿来找她谈些话.汉英文学 - 家（1-26） - 家（1-26）Sister - in - law told Hai - erh to greet me and wish me good morning.她说了又叫海儿给我请安.汉英文学 - 家（1-26） - 家（1-26）And can't Yao Chin - feng go one better than Chou Erh - chieh?难道 姚金凤 抵不过他们那周二姐么?子夜部分He taught me pen - ssu - erh and pen.铅笔叫‘喷丝儿’,钢笔叫‘盆’.汉英文学 - 中国现代小说Ming - feng whispered a few words in Wan - erh's ear.鸣凤半害羞地在婉儿的耳边说了一句话.汉英文学 - 家（1-26） - 家（1-26）Hei - erh . . . . Hei - erh.“到,到,到. ”汉英文学 - 中国现代小说But I never learned this hei - erh.可是没学过‘黑耳’. ”汉英文学 - 中国现代小说Chou Erh - chieh and Chien Chiaolin?周二姐和钱巧林么?子夜部分What did Hsueh Pao - chu and Chou Erh - chieh say?薛 宝珠 和周二姐说些什么呀?子夜部分Ming - feng didn't answer, and Wan - erh gently pressed, " You are in love, aren't you?鸣凤 并不回答.婉儿更委婉地低声追问: “ 你是不是心上有了人?汉英文学 - 家（1-26） - 家（1-26）The nursemaid brought Hai - erh in , and Sister - in - law played with him , while continuing to chat with me.“这时何嫂把海儿带了进来. 嫂嫂 便逗着海儿玩, 一面和我闲谈.汉英文学 - 家（1-26） - 家（1-26）" Chien - erh was looking for you a while back . I don't know what she wanted. "“ 刚才倩儿在找你,不晓得有什么事情, ” 觉慧说.汉英文学 - 家（1-26） - 家（1-26）收起实用场景例句释义实用场

Environmental Research: Health - IOPscience

Environmental Research: Health - IOPscience

Skip to content

Accessibility Links

Skip to content

Skip to search IOPscience

Skip to Journals list

Accessibility help

IOP Science home

Accessibility Help

Search

Journals

Journals list

Browse more than 100 science journal titles

Subject collections

Read the very best research published in IOP journals

Publishing partners

Partner organisations and publications

Open access

IOP Publishing open access policy guide

IOP Conference Series

Read open access proceedings from science conferences worldwide

Books

Publishing Support

Login

IOPscience login / Sign Up

Click here to close this panel.

Search

Primary search

Search all IOPscience content

Article Lookup

Select journal (required)

Select journal (required)2D Mater. (2014 - present)Acta Phys. Sin. (Overseas Edn) (1992 - 1999)Adv. Nat. Sci: Nanosci. Nanotechnol. (2010 - present)Appl. Phys. Express (2008 - present)Biofabrication (2009 - present)Bioinspir. Biomim. (2006 - present)Biomed. Mater. (2006 - present)Biomed. Phys. Eng. Express (2015 - present)Br. J. Appl. Phys. (1950 - 1967)Chin. J. Astron. Astrophys. (2001 - 2008)Chin. J. Chem. Phys. (1987 - 2007)Chin. J. Chem. Phys. (2008 - 2012)Chinese Phys. (2000 - 2007)Chinese Phys. B (2008 - present)Chinese Phys. C (2008 - present)Chinese Phys. Lett. (1984 - present)Class. Quantum Grav. (1984 - present)Clin. Phys. Physiol. Meas. (1980 - 1992)Combustion Theory and Modelling (1997 - 2004)Commun. Theor. Phys. (1982 - present)Comput. Sci. Discov. (2008 - 2015)Converg. Sci. Phys. Oncol. (2015 - 2018)Distrib. Syst. Engng. (1993 - 1999)ECS Adv. (2022 - present)ECS Electrochem. Lett. (2012 - 2015)ECS J. Solid State Sci. Technol. (2012 - present)ECS Sens. Plus (2022 - present)ECS Solid State Lett. (2012 - 2015)ECS Trans. (2005 - present)EPL (1986 - present)Electrochem. Soc. Interface (1992 - present)Electrochem. Solid-State Lett. (1998 - 2012)Electron. Struct. (2019 - present)Eng. Res. Express (2019 - present)Environ. Res. Commun. (2018 - present)Environ. Res. Lett. (2006 - present)Environ. Res.: Climate (2022 - present)Environ. Res.: Ecology (2022 - present)Environ. Res.: Energy (2024 - present)Environ. Res.: Food Syst. (2024 - present)Environ. Res.: Health (2022 - present)Environ. Res.: Infrastruct. Sustain. (2021 - present)Eur. J. Phys. (1980 - present)Flex. Print. Electron. (2015 - present)Fluid Dyn. Res. (1986 - present)Funct. Compos. Struct. (2018 - present)IOP Conf. Ser.: Earth Environ. Sci. (2008 - present)IOP Conf. Ser.: Mater. Sci. Eng. (2009 - present)IOPSciNotes (2020 - 2022)Int. J. Extrem. Manuf. (2019 - present)Inverse Problems (1985 - present)Izv. Math. (1993 - present)J. Breath Res. (2007 - present)J. Cosmol. Astropart. Phys. (2003 - present)J. Electrochem. Soc. (1902 - present)J. Geophys. Eng. (2004 - 2018)J. High Energy Phys. (1997 - 2009)J. Inst. (2006 - present)J. Micromech. Microeng. (1991 - present)J. Neural Eng. (2004 - present)J. Nucl. Energy, Part C Plasma Phys. (1959 - 1966)J. Opt. (1977 - 1998)J. Opt. (2010 - present)J. Opt. A: Pure Appl. Opt. (1999 - 2009)J. Opt. B: Quantum Semiclass. Opt. (1999 - 2005)J. Phys. A: Gen. Phys. (1968 - 1972)J. Phys. A: Math. Gen. (1975 - 2006)J. Phys. A: Math. Nucl. Gen. (1973 - 1974)J. Phys. A: Math. Theor. (2007 - present)J. Phys. B: At. Mol. Opt. Phys. (1988 - present)J. Phys. B: Atom. Mol. Phys. (1968 - 1987)J. Phys. C: Solid State Phys. (1968 - 1988)J. Phys. Commun. (2017 - present)J. Phys. Complex. (2019 - present)J. Phys. D: Appl. Phys. (1968 - present)J. Phys. E: Sci. Instrum. (1968 - 1989)J. Phys. Energy (2018 - present)J. Phys. F: Met. Phys. (1971 - 1988)J. Phys. G: Nucl. Part. Phys. (1989 - present)J. Phys. G: Nucl. Phys. (1975 - 1988)J. Phys. Mater. (2018 - present)J. Phys. Photonics (2018 - present)J. Phys.: Condens. Matter (1989 - present)J. Phys.: Conf. Ser. (2004 - present)J. Radiol. Prot. (1988 - present)J. Sci. Instrum. (1923 - 1967)J. Semicond. (2009 - present)J. Soc. Radiol. Prot. (1981 - 1987)J. Stat. Mech. (2004 - present)JoT (2000 - 2004)Jpn. J. Appl. Phys. (1962 - present)Laser Phys. (2013 - present)Laser Phys. Lett. (2004 - present)Mach. Learn.: Sci. Technol. (2019 - present)Mater. Futures (2022 - present)Mater. Quantum. Technol. (2020 - present)Mater. Res. Express (2014 - present)Math. USSR Izv. (1967 - 1992)Math. USSR Sb. (1967 - 1993)Meas. Sci. Technol. (1990 - present)Meet. Abstr. (2002 - present)Methods Appl. Fluoresc. (2013 - present)Metrologia (1965 - present)Modelling Simul. Mater. Sci. Eng. (1992 - present)Multifunct. Mater. (2018 - 2022)Nano Ex. (2020 - present)Nano Futures (2017 - present)Nanotechnology (1990 - present)Network (1990 - 2004)Neuromorph. Comput. Eng. (2021 - present)New J. Phys. (1998 - present)Nonlinearity (1988 - present)Nouvelle Revue d'Optique (1973 - 1976)Nouvelle Revue d'Optique Appliquée (1970 - 1972)Nucl. Fusion (1960 - present)PASP (1889 - present)Phys. Biol. (2004 - present)Phys. Bull. (1950 - 1988)Phys. Educ. (1966 - present)Phys. Med. Biol. (1956 - present)Phys. Scr. (1970 - present)Phys. World (1988 - present)Phys.-Usp. (1993 - present)Physics in Technology (1973 - 1988)Physiol. Meas. (1993 - present)Plasma Phys. Control. Fusion (1984 - present)Plasma Physics (1967 - 1983)Plasma Res. Express (2018 - 2022)Plasma Sci. Technol. (1999 - present)Plasma Sources Sci. Technol. (1992 - present)Proc. Phys. Soc. (1926 - 1948)Proc. Phys. Soc. (1958 - 1967)Proc. Phys. Soc. A (1949 - 1957)Proc. Phys. Soc. B (1949 - 1957)Proc. Phys. Soc. London (1874 - 1925)Proc. Vol. (1967 - 2005)Prog. Biomed. Eng. (2018 - present)Prog. Energy (2018 - present)Public Understand. Sci. (1992 - 2002)Pure Appl. Opt. (1992 - 1998)Quantitative Finance (2001 - 2004)Quantum Electron. (1993 - present)Quantum Opt. (1989 - 1994)Quantum Sci. Technol. (2015 - present)Quantum Semiclass. Opt. (1995 - 1998)Rep. Prog. Phys. (1934 - present)Res. Astron. Astrophys. (2009 - present)Research Notes of the AAS (2017 - present)RevPhysTech (1970 - 1972)Russ. Chem. Rev. (1960 - present)Russ. Math. Surv. (1960 - present)Sb. Math. (1993 - present)Sci. Technol. Adv. Mater. (2000 - 2015)Semicond. Sci. Technol. (1986 - present)Smart Mater. Struct. (1992 - present)Sov. J. Quantum Electron. (1971 - 1992)Sov. Phys. Usp. (1958 - 1992)Supercond. Sci. Technol. (1988 - present)Surf. Topogr.: Metrol. Prop. (2013 - present)Sustain. Sci. Technol. (2024 - present)The Astronomical Journal (1849 - present)The Astrophysical Journal (1996 - present)The Astrophysical Journal Letters (2010 - present)The Astrophysical Journal Supplement Series (1996 - present)The Planetary Science Journal (2020 - present)Trans. Amer: Electrochem. Soc. (1930 - 1930)Trans. Electrochem. Soc. (1931 - 1948)Trans. Opt. Soc. (1899 - 1932)Transl. Mater. Res. (2014 - 2018)Waves Random Media (1991 - 2004)

Volume number:

Issue number (if known):

Article or page number:

Purpose-led Publishing is a coalition of three not-for-profit publishers in the field of physical sciences: AIP Publishing, the American Physical Society and IOP Publishing.

Together, as publishers that will always put purpose above profit, we have defined a set of industry standards that underpin high-quality, ethical scholarly communications.

We are proudly declaring that science is our only shareholder.

ISSN: 2752-5309

OPEN ACCESS

Environmental Research: Health is a multidisciplinary, open access journal devoted to addressing important global challenges at the interface of the environment and public health in a way that bridges scientific progress and assessment with efforts relating to impact/future risks, resilience, mitigation, adaptation, security and solutions in the broadest sense. All research methodologies are encouraged comprehensively covering qualitative, quantitative, experimental, theoretical and applied approaches; exposure assessments; implementation studies; and policy analysis. For detailed information about subject coverage see the About the journal section.

Register to watch recordings of sessions from Environmental Research 2023 on-demand

Free for readers. All article publication charges are currently paid by IOP Publishing.

Submit

an article

opens in new tab

Track my article opens in new tab

RSS

Sign up for new issue notifications

Current volume

Number 2, June 2024Number 1, March 2024

Journal archive

Vol 2, 2024Vol 1, 2023

Focus issues

Focus on Environmental Health and DisastersFocus on Environmental Sustainability and Health CareFocus on Natural Hazards, Disasters, and Extreme EventsFocus on Climate Change Extreme Weather and Health

Most read

Latest articles

Review articles

Accepted manuscripts

Trending

Most read

Open all abstracts, in this tab

The following article is Open access

Air pollution and health impacts of oil & gas production in the United States

Jonathan J Buonocore et al 2023 Environ. Res.: Health 1 021006

Open abstract

View article, Air pollution and health impacts of oil & gas production in the United States

PDF, Air pollution and health impacts of oil & gas production in the United States

Oil and gas production is one of the largest emitters of methane, a potent greenhouse gas and a significant contributor of air pollution emissions. While research on methane emissions from oil and gas production has grown rapidly, there is comparatively limited information on the distribution of impacts of this sector on air quality and associated health impacts. Understanding the contribution of air quality and health impacts of oil and gas can be useful for designing mitigation strategies. Here we assess air quality and human health impacts associated with ozone, fine particulate matter, and nitrogen dioxide from the oil and gas sector in the US in 2016, and compare this impact with that of the associated methane emissions. We find that air pollution in 2016 from the oil and gas sector in the US resulted in 410 000 asthma exacerbations, 2200 new cases of childhood asthma and 7500 excess deaths, with $77 billion in total health impacts. NO2 was the highest contributor to health impacts (37%) followed by ozone (35%), and then PM2.5 (28%). When monetized, these air quality health impacts of oil and gas production exceeded estimated climate impact costs from methane leakage by a factor of 3. These impacts add to the total life cycle impacts of oil and gas, and represent potential additional health benefits of strategies that reduce consumption of oil and gas. Policies to reduce oil and gas production emissions will lead to additional and significant health benefits from co-pollutant reductions that are not currently quantified or monetized.

https://doi.org/10.1088/2752-5309/acc886

The following article is Open access

An interrupted time series analysis of the cardiovascular health benefits of a coal coking operation closure

Wuyue Yu and George D Thurston 2023 Environ. Res.: Health 1 045002

Open abstract

View article, An interrupted time series analysis of the cardiovascular health benefits of a coal coking operation closure

PDF, An interrupted time series analysis of the cardiovascular health benefits of a coal coking operation closure

With the widespread implementation of air pollution mitigation strategies for health and climate policy, there is an emerging interest in accountability studies to validate whether a reduction of air pollution exposure, in fact, produces the human health benefits estimated from past air pollution epidemiology. The closure of a coal coking plant provides an ideal 'natural' experiment opportunity to rigorously evaluate the health benefits of air pollution emissions reductions. In this study, we applied an interrupted time series model to test the hypothesis that the substantial reduction in air pollution induced by the closure of the Shenango, Inc. coke plant in Pittsburgh, PA during January, 2016 was followed by immediate and/or longer-term cumulative local cardiovascular health benefits. We observed a 90% decrease in nearby SO2 levels, as well as significant reductions in coal-related fine particulate matter constituents (sulfate and arsenic), after the closure. Statistically significant cardiovascular health benefits were documented in the local population, including a 42% immediate drop (95% CI: 33%, 51%) in cardiovascular emergency department (ED) visits from the pre-closure mean. A longer-term downward trend was also observed for overall emergency visits at −0.14 (95% CI: −0.17, −0.11) visits per week rate of decrease after the closure, vs. a rise of 0.17 (95% CI: 0.14, 0.20) visits per week before. Similarly, inpatient cardiovascular hospitalizations per year showed a decrease after closure (−27.97 [95% CI: −46.90, −9.04], as compared with a 5.09 [95% CI: −13.84, 24.02] average increase in cases/year over the prior three years). Our study provides clear evidence that this intervention lowering fossil fuel-associated air pollution benefited public health in both the short and longer term, while also providing validation of the past use of observational air pollution epidemiology effect estimates in policy analyses.

https://doi.org/10.1088/2752-5309/ace4ea

The following article is Open access

Air pollution related adverse respiratory health outcomes in California's San Joaquin Valley: evidence from 2016 linked emergency department and hospital records

Gilda Zarate-Gonzalez et al 2024 Environ. Res.: Health 2 025003

Open abstract

View article, Air pollution related adverse respiratory health outcomes in California's San Joaquin Valley: evidence from 2016 linked emergency department and hospital records

PDF, Air pollution related adverse respiratory health outcomes in California's San Joaquin Valley: evidence from 2016 linked emergency department and hospital records

The San Joaquin Valley (SJV) of California has been consistently identified as having one of the highest levels of air pollution in the US. Despite federal and state standards, the SJV has been in non-attainment status for daily PM2.5 concentrations, extreme non-attainment for 8 hr O3 levels, and attainment for NO2. An epidemiological time-stratified case-crossover design was used to estimate the relationship between exposure to NO2, O3, PM2.5 and adverse health outcomes in asthma and upper respiratory infections (URIs). This study compared pollutant exposure effects for each case during limited time intervals and adjusted for seasonality. Elevated concentrations of three criteria outdoor air pollutants are associated with increased asthma and URI-related ED visits and hospitalizations in the SJV for all ages. NO2 exposure increased the odds of having an ED visit by 2.4% in lag 1 (95% CI: 1.017, 1.031). Lags 2, 3, 4, 5, 7, 9, and 14 were statistically significant. O3 modestly increased the odds of ED visits by 0.3% (95% CI:1.000, 1.006) after immediate exposure in the warm season. In the cold season, PM2.5 estimates were significant for all lags except for lags 4 and 12. The two-week lag increased the odds by 28% (95% CI:1.218, 1.345) for ED visits, and 16.5% (95% CI:1.009, 1.345) increased the odds of being hospitalized after cumulative exposure to PM2.5. Findings suggest that SJV residents experience adverse health effects due to elevated exposure to NO2 despite attainment of federal and state pollutant standards. This study provides new evidence about the effects of three criteria air pollutants and adverse health outcomes in the SJV region. The air quality regulatory and public health governing bodies should consider revisions to regional pollutant thresholds and local public health strategies to prevent adverse health outcomes during short and prolonged periods of air pollution exposure.

https://doi.org/10.1088/2752-5309/ad268a

The following article is Open access

Using low-cost air quality sensors to estimate wildfire smoke infiltration into childcare facilities in British Columbia, Canada

Michael Joseph Lee et al 2024 Environ. Res.: Health 2 025002

Open abstract

View article, Using low-cost air quality sensors to estimate wildfire smoke infiltration into childcare facilities in British Columbia, Canada

PDF, Using low-cost air quality sensors to estimate wildfire smoke infiltration into childcare facilities in British Columbia, Canada

The health risks associated with wildfires are expected to increase due to climate change. Children are susceptible to wildfire smoke, but little is known about indoor smoke exposure at childcare facilities. The objective of this analysis was to estimate the effects of outdoor PM2.5 and wildfire smoke episodes on indoor PM2.5 at childcare facilities across British Columbia, Canada. We installed low-cost air-quality sensors inside and outside 45 childcare facilities and focused our analysis on operational hours (Monday–Friday, 08:00–18:00) during the 2022 wildfire season (01 August–31 October). Using random-slope random-intercept linear mixed effects regression, we estimated the overall and facility-specific effects of outdoor PM2.5 on indoor PM2.5, while accounting for covariates. We examined how wildfire smoke affected this relationship by separately analyzing days with and without wildfire smoke. Average indoor PM2.5 increased by 235% on wildfire days across facilities. There was a positive relationship between outdoor and indoor PM2.5 that was not strongly influenced by linear adjustment for meteorological and area-based socio-economic factors. A 1.0 μg m−3 increase in outdoor PM2.5 was associated with a 0.55 μg m−3 [95% CI: 0.47, 0.63] increase indoors on non-wildfire smoke days and 0.51 μg m−3 [95% CI: 0.44, 0.58] on wildfire-smoke days. Facility-specific regression coefficients of the effect of outdoor PM2.5 on indoor PM2.5 was variable between facilities on wildfire (0.18–0.79 μg m−3) and non-wildfire days (0.11–1.03 μg m−3). Indoor PM2.5 responded almost immediately to increased outdoor PM2.5 concentrations. Across facilities, 89% and 93% of the total PM2.5 infiltration over 60 min occurred within the first 10 min following an increase in outdoor PM2.5 on non-wildfire and wildfire days, respectively. We found that indoor PM2.5 in childcare facilities increased with outdoor PM2.5. This effect varied between facilities and between wildfire-smoke and non-wildfire smoke days. These findings highlight the importance of air quality monitoring at childcare facilities for informed decision-making.

https://doi.org/10.1088/2752-5309/ad1fd6

The following article is Open access

Intervention studies to reduce the impact of climate change on health in rural communities in the United States: a systematic review

Daniel J Smith et al 2023 Environ. Res.: Health 1 032001

Open abstract

View article, Intervention studies to reduce the impact of climate change on health in rural communities in the United States: a systematic review

PDF, Intervention studies to reduce the impact of climate change on health in rural communities in the United States: a systematic review

Climate change, the greatest public health threat of the 21st century, will uniquely affect rural areas that are geographically isolated and experience greater health inequities. This systematic review describes and evaluates interventions to lessen the effects of climate change on human health in the rural United States, including interventions on air pollution, vector ecology, water quality, severe weather, extreme heat, allergens, and water and food supply. Searches were constructed based on the eight domains of the Centers for Disease Control and Prevention (CDC) Framework "Impact of Climate Change on Human Health." Searches were conducted in EBSCO Environment Complete, EBSCO GreenFILE, Embase.com, MEDLINE via PubMed, and Web of Science. Duplicate citations were removed, abstracts were screened for initial inclusion, and full texts were screened for final inclusion. Pertinent data were extracted and synthesized across the eight domains. Article quality was assessed using the Mixed Methods Appraisal Tool. Of 8471 studies screened, 297 were identified for full text review, and a total 49 studies were included in this review. Across the domains, 34 unique interventions addressed health outcomes due to air pollution (n = 8), changes in vector ecology (n = 6), water quality (n = 5), severe weather (n = 3), extreme heat (n = 2) increasing allergens (n = 1), water and food supply (n = 1), and across multiple CDC domains (n = 8). Participatory action research methodology was commonly used and strived to mobilize/empower communities to tackle climate change. Our review identified three randomized controlled trials, with two of these three published in the last five years. While original research on the impact of climate change on health has increased in the past decade, randomized control trials may not be ethical, cost effective, or feasible. There is a need for time-efficient and high-quality scholarship that investigates intervention efficacy and effectiveness for reducing health impacts of climate change upon rural populations.

https://doi.org/10.1088/2752-5309/acbbe6

The following article is Open access

Outside in: the relationship between indoor and outdoor particulate air quality during wildfire smoke events in western US cities

Katelyn O'Dell et al 2023 Environ. Res.: Health 1 015003

Open abstract

View article, Outside in: the relationship between indoor and outdoor particulate air quality during wildfire smoke events in western US cities

PDF, Outside in: the relationship between indoor and outdoor particulate air quality during wildfire smoke events in western US cities

Previous research on the health and air quality impacts of wildfire smoke has largely focused on the impact of smoke on outdoor air quality; however, many people spend a majority of their time indoors. The quality of indoor air on smoke-impacted days is largely unknown. In this analysis, we use publicly available data from an existing large network of low-cost indoor and outdoor fine particulate matter (PM2.5) monitors to quantify the relationship between indoor and outdoor particulate air quality on smoke-impacted days in 2020 across the western United States (US). We also investigate possible regional and socioeconomic trends in this relationship for regions surrounding six major cities in the western US. We find indoor PM2.5 concentrations are 82% or 4.2 µg m−3 (median across all western US indoor monitors for the year 2020; interquartile range, IQR: 2.0–7.2 µg m−3) higher on smoke-impacted days compared to smoke-free days. Indoor/outdoor PM2.5 ratios show variability by region, particularly on smoke-free days. However, we find the ratio of indoor/outdoor PM2.5 is less than 1 (i.e. indoor concentrations lower than outdoor) at nearly all indoor-outdoor monitor pairs on smoke-impacted days. Although typically lower than outdoor concentrations on smoke-impacted days, we find that on heavily smoke-impacted days (outdoor PM2.5 > 55 µg m−3), indoor PM2.5 concentrations can exceed the 35 µg m−3 24 h outdoor standard set by the US Environmental Protection Agency. Further, total daily-mean indoor PM2.5 concentrations increase by 2.1 µg m−3 with every 10 µg m−3 increase in daily-mean outdoor PM2.5. (median of statistically significant linear regression slopes across all western US monitor pairs; IQR: 1.0–4.3 µg m−3) on smoke-impacted days. These results show that for indoor environments in the western US included in our analysis, remaining indoors during smoke events is currently an effective, but limited, strategy to reduce PM2.5 exposure.

https://doi.org/10.1088/2752-5309/ac7d69

The following article is Open access

Air quality and health effects of a transition to ammonia–fueled shipping in Singapore

Sagar Rathod et al 2023 Environ. Res.: Health 1 041002

Open abstract

View article, Air quality and health effects of a transition to ammonia–fueled shipping in Singapore

PDF, Air quality and health effects of a transition to ammonia–fueled shipping in Singapore

Ammonia has been proposed to replace heavy fuel oil (HFO) in the shipping industry by 2050. When produced with low-carbon electricity, ammonia can reduce greenhouse gas emissions. However, ammonia emissions also contribute to local air pollution via the formation of secondary particulate matter. We estimate the potential ammonia emissions from storage and bunkering operations for shipping in Singapore, a port that accounts for 20% of global bunker fuel sales, and their impacts on air quality and health. Fuel storage and bunkering can increase total gaseous ammonia emissions in Singapore by up to a factor of four and contribute to a 25%–50% increase in ambient PM2.5 concentration compared to a baseline scenario with HFO, leading to an estimated 210–460 premature mortalities in Singapore (30%–70% higher than the baseline). Proper abatement on storage and bunkering can reduce these emissions and even improve ambient PM2.5 concentrations compared to the baseline. Overall, while an energy transition from HFO to ammonia in the shipping industry could reduce global greenhouse gas and air pollutant burdens, local policies will be important to avoid negative impacts on the communities living near its supply chain.

https://doi.org/10.1088/2752-5309/acfb2e

The following article is Open access

After the fire: A qualitative study of the role of long-term recovery organizations in addressing rural communities' post-wildfire needs

Kathleen Moloney et al 2023 Environ. Res.: Health 1 021009

Open abstract

View article, After the fire: A qualitative study of the role of long-term recovery organizations in addressing rural communities' post-wildfire needs

PDF, After the fire: A qualitative study of the role of long-term recovery organizations in addressing rural communities' post-wildfire needs

U.S. wildfire activity has increased over the past several decades, disrupting the systems and infrastructure that support community health and resilience. As the cumulative burden of wildfire damage is projected to increase, understanding an effective community recovery process is critically important. Through qualitative interviews with leaders of long-term recovery organizations (LTROs), a key component of wildfire recovery, we explored barriers and facilitators to LTROs' ability to support post-wildfire needs among rural communities. Between February-May 2022, we conducted surveys and semi-structured interviews with 18 leaders from six LTROs serving rural communities in Washington, Oregon, and California impacted by wildfires between 2015–2020. The Robert Wood Johnson Foundation's Culture of Health Framework informed the semi-structured interview guide and a priori codebook, to examine LTROs' ability to address post-wildfire community needs from a health equity perspective. Additional codes were added through an inductive approach, and emerging themes were identified. Our findings indicate that LTROs face many barriers in addressing community needs post-wildfire, including the policies governing access to and the slow arrival of recovery resources, the intertwined nature of community economic health and built environment restoration, and the challenge of forming a functional LTRO structure. However, participants also identified facilitators of LTROs' work, including the ability of LTROs and their government partners to adapt policies and procedures, and close collaboration with other community organizations. Factors both internal and external to the community and LTROs' organizational characteristics influence their ability to address community needs, essential to health, post-wildfire. This study's findings suggest the need for policy improvements to promote more equitable recovery resource access, that economic recovery should be a core LTRO function, and that recovery planning should be incorporated into community disaster preparedness activities. Future research should focus on LTROs' role in other contexts and in response to other disasters.

https://doi.org/10.1088/2752-5309/acd2f7

The following article is Open access

Air quality and health co-benefits of climate change mitigation and adaptation actions by 2030: an interdisciplinary modeling study in Ahmedabad, India

Vijay S Limaye et al 2023 Environ. Res.: Health 1 021003

Open abstract

View article, Air quality and health co-benefits of climate change mitigation and adaptation actions by 2030: an interdisciplinary modeling study in Ahmedabad, India

PDF, Air quality and health co-benefits of climate change mitigation and adaptation actions by 2030: an interdisciplinary modeling study in Ahmedabad, India

Climate change-driven temperature increases worsen air quality in places where coal combustion powers electricity for air conditioning. Climate solutions that substitute clean and renewable energy in place of polluting coal and promote adaptation to warming through reflective cool roofs can reduce cooling energy demand in buildings, lower power sector carbon emissions, and improve air quality and health. We investigate the air quality and health co-benefits of climate solutions in Ahmedabad, India—a city where air pollution levels exceed national health-based standards—through an interdisciplinary modeling approach. Using a 2018 baseline, we quantify changes in fine particulate matter (PM2.5) air pollution and all-cause mortality in 2030 from increasing renewable energy use (mitigation) and expanding Ahmedabad's cool roofs heat resilience program (adaptation). We apply local demographic and health data and compare a 2030 mitigation and adaptation (M&A) scenario to a 2030 business-as-usual (BAU) scenario (without climate change response actions), each relative to 2018 pollution levels. We estimate that the 2030 BAU scenario results in an increase of PM2.5 air pollution of 4.13 µg m−3 from 2018 compared to a 0.11 µg m−3 decline from 2018 under the 2030 M&A scenario. Reduced PM2.5 air pollution under 2030 M&A results in 1216–1414 fewer premature all-cause deaths annually compared to 2030 BAU. Achievement of National Clean Air Programme, National Ambient Air Quality Standards, or World Health Organization annual PM2.5 Air Quality Guideline targets in 2030 results in up to 6510, 9047, or 17 369 fewer annual deaths, respectively, relative to 2030 BAU. This comprehensive modeling method is adaptable to estimate local air quality and health co-benefits in other settings by integrating climate, energy, cooling, land cover, air pollution, and health data. Our findings demonstrate that city-level climate change response policies can achieve substantial air quality and health co-benefits. Such work can inform public discourse on the near-term health benefits of mitigation and adaptation.

https://doi.org/10.1088/2752-5309/aca7d8

The following article is Open access

Effect modification of the association between fine particulate air pollution during a wildfire event and respiratory health by area-level measures of socio-economic status, race/ethnicity, and smoking prevalence

C E Reid et al 2023 Environ. Res.: Health 1 025005

Open abstract

View article, Effect modification of the association between fine particulate air pollution during a wildfire event and respiratory health by area-level measures of socio-economic status, race/ethnicity, and smoking prevalence

PDF, Effect modification of the association between fine particulate air pollution during a wildfire event and respiratory health by area-level measures of socio-economic status, race/ethnicity, and smoking prevalence

Fine particulate air pollution (PM2.5) is decreasing in most areas of the United States, except for areas most affected by wildfires, where increasing trends in PM2.5 can be attributed to wildfire smoke. The frequency and duration of large wildfires and the length of the wildfire season have all increased in recent decades, partially due to climate change, and wildfire risk is projected to increase further in many regions including the western United States. Increasingly, empirical evidence suggests differential health effects from air pollution by class and race; however, few studies have investigated such differential health impacts from air pollution during a wildfire event. We investigated differential risk of respiratory health impacts during the 2008 northern California wildfires by a comprehensive list of socio-economic status (SES), race/ethnicity, and smoking prevalence variables. Regardless of SES level across nine measures of SES, we found significant associations between PM2.5 and asthma hospitalizations and emergency department (ED) visits during these wildfires. Differential respiratory health risk was found by SES for ED visits for chronic obstructive pulmonary disease where the highest risks were in ZIP codes with the lowest SES levels. Findings for differential effects by race/ethnicity were less consistent across health outcomes. We found that ZIP codes with higher prevalence of smokers had greater risk of ED visits for asthma and pneumonia. Our study suggests that public health efforts to decrease exposures to high levels of air pollution during wildfires should focus on lower SES communities.

https://doi.org/10.1088/2752-5309/acc4e1

Latest articles

Open all abstracts, in this tab

The following article is Open access

Temperature and hospital admissions in the Eastern Mediterranean: a case study in Cyprus

Yichen Wang et al 2024 Environ. Res.: Health 2 025004

Open abstract

View article, Temperature and hospital admissions in the Eastern Mediterranean: a case study in Cyprus

PDF, Temperature and hospital admissions in the Eastern Mediterranean: a case study in Cyprus

Exposure to extreme temperatures can trigger a cascade of adverse cardiovascular and respiratory events. However, in Cyprus, a hotspot of climate change in the Eastern Mediterranean region, little is known about the temperature-related cardiorespiratory morbidity risks. We analyzed daily counts of hospital admissions for cardiovascular and respiratory diseases from four general hospitals in three districts in Cyprus from 2000 through 2019. For each district, we fitted time-series quasi-Poisson regression with distributed lag non-linear models to analyze the associations between daily mean temperature (lag 0–21 d) and hospital admissions for cardiorespiratory, cardiovascular, and respiratory diseases. A random-effects meta-analytical model was then applied to pool the district-specific estimates and obtain the national average associations. We analyzed 20 years of cause-specific hospitalization data with a total of 179 988 cardiovascular and respiratory events. The relationships between cardiorespiratory morbidity and temperature were overall U-shaped. During extreme temperature days, 15.85% (95% empirical CI [eCI]: 8.24, 22.40%) excess cardiovascular hospitalizations and 9.59% (95% eCI: −0.66, 18.69%) excess respiratory hospitalizations were attributable to extreme cold days (below the 2.5th percentile). Extreme hot days (above the 97.5th percentile) accounted for 0.17% (95% eCI: 0.03, 0.29%) excess cardiovascular hospitalizations and 0.23% (95% eCI: 0.07, 0.35%) excess respiratory hospitalizations. We found evidence of increased cardiovascular morbidity risk associated with extreme temperatures in Cyprus. Our study highlights the necessity to implement public health interventions and adaptive measures to mitigate the related temperature effects in an understudied region.

https://doi.org/10.1088/2752-5309/ad2780

The following article is Open access

Air pollution related adverse respiratory health outcomes in California's San Joaquin Valley: evidence from 2016 linked emergency department and hospital records

Gilda Zarate-Gonzalez et al 2024 Environ. Res.: Health 2 025003

Open abstract

View article, Air pollution related adverse respiratory health outcomes in California's San Joaquin Valley: evidence from 2016 linked emergency department and hospital records

PDF, Air pollution related adverse respiratory health outcomes in California's San Joaquin Valley: evidence from 2016 linked emergency department and hospital records

The San Joaquin Valley (SJV) of California has been consistently identified as having one of the highest levels of air pollution in the US. Despite federal and state standards, the SJV has been in non-attainment status for daily PM2.5 concentrations, extreme non-attainment for 8 hr O3 levels, and attainment for NO2. An epidemiological time-stratified case-crossover design was used to estimate the relationship between exposure to NO2, O3, PM2.5 and adverse health outcomes in asthma and upper respiratory infections (URIs). This study compared pollutant exposure effects for each case during limited time intervals and adjusted for seasonality. Elevated concentrations of three criteria outdoor air pollutants are associated with increased asthma and URI-related ED visits and hospitalizations in the SJV for all ages. NO2 exposure increased the odds of having an ED visit by 2.4% in lag 1 (95% CI: 1.017, 1.031). Lags 2, 3, 4, 5, 7, 9, and 14 were statistically significant. O3 modestly increased the odds of ED visits by 0.3% (95% CI:1.000, 1.006) after immediate exposure in the warm season. In the cold season, PM2.5 estimates were significant for all lags except for lags 4 and 12. The two-week lag increased the odds by 28% (95% CI:1.218, 1.345) for ED visits, and 16.5% (95% CI:1.009, 1.345) increased the odds of being hospitalized after cumulative exposure to PM2.5. Findings suggest that SJV residents experience adverse health effects due to elevated exposure to NO2 despite attainment of federal and state pollutant standards. This study provides new evidence about the effects of three criteria air pollutants and adverse health outcomes in the SJV region. The air quality regulatory and public health governing bodies should consider revisions to regional pollutant thresholds and local public health strategies to prevent adverse health outcomes during short and prolonged periods of air pollution exposure.

https://doi.org/10.1088/2752-5309/ad268a

The following article is Open access

Social media engagement in health and climate change: an exploratory analysis of Twitter

Su Golder and Hilary Graham 2024 Environ. Res.: Health 2 021001

Open abstract

View article, Social media engagement in health and climate change: an exploratory analysis of Twitter

PDF, Social media engagement in health and climate change: an exploratory analysis of Twitter

Social media are increasingly used by the public to share information and opinions. This study explores social media engagement in health and climate change through an analysis of English-language posts on Twitter, one of the most widely-used platforms. We searched Twitter from 21 March 2023 to 11 May 2023 for posts related to climate change using climate-related textwords and hashtags; we then used health keywords ('health', 'wellbeing', 'illness', 'illnesses', 'disease', 'death') to identify posts related to health. Focusing on posts from general public users, we investigated the proportion of climate change posts referring to health and, for a random sample of these tweets, undertook a content analysis to identify the ways in which climate change and health were represented. The content analysis drew on media research on 'framing', a selective process through which particular aspects of an issue—for example, its causes, impacts and solutions—are highlighted. 668 810 posts related to climate change were posted during the study period. Health-related text words were included in 2.3% (15 434) of these posts. The content analysis pointed to two divergent frames. The first frame represents climate change as real, with real effects on people's health. The second frame portrays climate change as a hoax, with hoax-generated health effects. While the 'reality' frame does not engage with the hoax frame, the latter provides an insistent counter-narrative that questions trust in mainstream science and government policy. Neither frame engages with people's experiences of health and climate change. In conclusion, our study points to low levels of engagement in health in a key forum for public discussions about climate change. It also asks whether the failure of the 'reality' frame to engage either with people's lived experiences or with hoax framings may be contributing to a polarised debate about climate change and health and hindering consensus-building.

https://doi.org/10.1088/2752-5309/ad22ea

The following article is Open access

Using low-cost air quality sensors to estimate wildfire smoke infiltration into childcare facilities in British Columbia, Canada

Michael Joseph Lee et al 2024 Environ. Res.: Health 2 025002

Open abstract

View article, Using low-cost air quality sensors to estimate wildfire smoke infiltration into childcare facilities in British Columbia, Canada

PDF, Using low-cost air quality sensors to estimate wildfire smoke infiltration into childcare facilities in British Columbia, Canada

The health risks associated with wildfires are expected to increase due to climate change. Children are susceptible to wildfire smoke, but little is known about indoor smoke exposure at childcare facilities. The objective of this analysis was to estimate the effects of outdoor PM2.5 and wildfire smoke episodes on indoor PM2.5 at childcare facilities across British Columbia, Canada. We installed low-cost air-quality sensors inside and outside 45 childcare facilities and focused our analysis on operational hours (Monday–Friday, 08:00–18:00) during the 2022 wildfire season (01 August–31 October). Using random-slope random-intercept linear mixed effects regression, we estimated the overall and facility-specific effects of outdoor PM2.5 on indoor PM2.5, while accounting for covariates. We examined how wildfire smoke affected this relationship by separately analyzing days with and without wildfire smoke. Average indoor PM2.5 increased by 235% on wildfire days across facilities. There was a positive relationship between outdoor and indoor PM2.5 that was not strongly influenced by linear adjustment for meteorological and area-based socio-economic factors. A 1.0 μg m−3 increase in outdoor PM2.5 was associated with a 0.55 μg m−3 [95% CI: 0.47, 0.63] increase indoors on non-wildfire smoke days and 0.51 μg m−3 [95% CI: 0.44, 0.58] on wildfire-smoke days. Facility-specific regression coefficients of the effect of outdoor PM2.5 on indoor PM2.5 was variable between facilities on wildfire (0.18–0.79 μg m−3) and non-wildfire days (0.11–1.03 μg m−3). Indoor PM2.5 responded almost immediately to increased outdoor PM2.5 concentrations. Across facilities, 89% and 93% of the total PM2.5 infiltration over 60 min occurred within the first 10 min following an increase in outdoor PM2.5 on non-wildfire and wildfire days, respectively. We found that indoor PM2.5 in childcare facilities increased with outdoor PM2.5. This effect varied between facilities and between wildfire-smoke and non-wildfire smoke days. These findings highlight the importance of air quality monitoring at childcare facilities for informed decision-making.

https://doi.org/10.1088/2752-5309/ad1fd6

The following article is Open access

Effects of air pollution on emergency room visits for mental disorders: risks and effect modification by comorbid physical disorders and personal characteristics

Eun-hye Yoo et al 2024 Environ. Res.: Health 2 025001

Open abstract

View article, Effects of air pollution on emergency room visits for mental disorders: risks and effect modification by comorbid physical disorders and personal characteristics

PDF, Effects of air pollution on emergency room visits for mental disorders: risks and effect modification by comorbid physical disorders and personal characteristics

Emerging evidence suggests that exposure to ambient air pollution negatively impacts mental health. However, little is known about potential moderators of such effects, including pre-existing physical disorders and personal characteristics. This study investigated if the effects of daily changes in levels of air pollutants among individuals with mental disorders (MDs) vary depending on comorbid physical disorders, age, sex, or race/ethnicity. We used a time-stratified case-crossover design that compared the levels of PM2.5 and NO2 on days leading up to MD-related emergency room (ER) visits to levels on control days. The sample consisted of individuals with MDs for their primary diagnosis, including both patients with a second diagnosis and those without. We conducted a stratified analysis to examine potential effect modifications by individuals' demographic characteristics (sex, age, and race/ethnicity) or a diagnosis of a physical disorder (cardiovascular disease, diabetes mellitus, and respiratory disease). We found that both PM2.5 and NO2 were significantly associated with ER visits for MDs. Per 10 µg m−3 increase in daily PM2.5 and per 10 ppb increase in NO2 concentration were associated with 1.07% (95% CI: 0.81%, 1.34%) and 0.56% (95% CI: 0.42%, 0.69%) increase in ER visits for MDs, respectively. We also found significantly greater susceptibility among younger persons (below 18 years old), Black, and individuals with respiratory disease. Exposures to both PM2.5 and NO2 were significantly associated with ER visits for MDs, and these adverse effects were more pronounced among youth, Black and individuals with respiratory disease as a comorbid physical disorder.

https://doi.org/10.1088/2752-5309/ad1f3f

Review articles

Open all abstracts, in this tab

The following article is Open access

Carbon dioxide as an indicator of bioaerosol activity and human health in K-12 school systems: a scoping review of current knowledge

Mayank Gangwar et al 2024 Environ. Res.: Health 2 012001

Open abstract

View article, Carbon dioxide as an indicator of bioaerosol activity and human health in K-12 school systems: a scoping review of current knowledge

PDF, Carbon dioxide as an indicator of bioaerosol activity and human health in K-12 school systems: a scoping review of current knowledge

Indoor air quality (IAQ) in schools has received attention over the past decades but still lacks specific standards and regulations. This study aimed to review the impact of bioaerosol activity in indoor environments on acute respiratory diseases and explore whether carbon dioxide can be used as an indicator of bioaerosol and respiratory diseases in indoor environments in K-12 school systems. Findings suggest a lack of a consensual approach to evaluate bioaerosols impacting IAQ in indoor infrastructures, particularly in school environments; an elevated CO2 concentration inside the school classrooms was not uncommon, and the evidence of unsatisfactory and degraded IAQ (surpassing ASHRAE standards) at public schools in rural and urban settings in one of the North Central County, Florida. It was found that CO2 levels can be associated with bioaerosol activity, and sufficient ventilation within the space substantially reduces the airborne time of respiratory droplets and CO2 levels. CO2 monitoring can act as an effective, low-cost alternative to surveying or detecting the prevalence of respiratory diseases, which may hold strength through establishing critical CO2 thresholds and, thereafter associating it with the infectious doses of pathogen activity.

https://doi.org/10.1088/2752-5309/ad1c41

The following article is Open access

Early-life oxidative stress due to air pollution. A scoping review focusing on identifying potential '-OMICS' biomarkers from body fluids

J V F Coumans and S Al Jaaidi 2023 Environ. Res.: Health 1 032002

Open abstract

View article, Early-life oxidative stress due to air pollution. A scoping review focusing on identifying potential '-OMICS' biomarkers from body fluids

PDF, Early-life oxidative stress due to air pollution. A scoping review focusing on identifying potential '-OMICS' biomarkers from body fluids

Exposure to air pollution (AP) is inevitable in daily life and an increasing number of epidemiological studies have reported that exposure to ambient particulate matter (PM) is associated with adverse health outcomes. Intrauterine, childhood, and adolescence are vulnerable periods, during which PM exposure can cause molecular changes, potentially leading to changes in metabolism and development. PM-induced oxidative stress is the underlying mechanism. Biomarkers can be used as illustrative measures of PM exposure to facilitate the assessment of potential health effects and provide a better understanding of the underlying mechanisms. The purpose of this scoping review is to report -OMICS biomarkers found in body fluids that are primarily related to oxidative stress and are already used to evaluate ambient AP exposure, as well as to identify knowledge gaps. Web of Science, PubMed, and Scopus databases were independently searched for all studies published between January 2013 and December 2022 that reported on -OMICS signature changes during pregnancy, childhood, and adolescence. Of the initial 757 articles, 36 met our inclusion criteria and reported on genomic, epigenomic, transcriptomic, proteomic, lipidomic, and metabolomic biomarkers. The findings of this scoping review indicate that exposure to various ambient pollutants in early life can cause oxidative stress. Integrating biomarkers from top-down -OMICS studies in an epidemiological context may provide a clear picture of the biomarker selection process to establish a causal relationship between PM exposure and disease pathogenesis. This knowledge could lead to the conceptualization and subsequent development of novel preventative strategies.

https://doi.org/10.1088/2752-5309/acdd18

The following article is Open access

Wildfires and the COVID-19 pandemic: a systematized literature review of converging health crises

Kathleen A Clark and Mary Sheehan 2023 Environ. Res.: Health 1 022002

Open abstract

View article, Wildfires and the COVID-19 pandemic: a systematized literature review of converging health crises

PDF, Wildfires and the COVID-19 pandemic: a systematized literature review of converging health crises

The emergence and global spread of the COVID-19 pandemic in 2020 converged with wildfire seasons of unprecedented extent. These co-occurring crises brought the potential for amplified health impacts. A systematized literature review was conducted to identify the health impacts from co-exposure to wildfires and the COVID-19 pandemic. A search of PubMed and Scopus identified 373 distinct references which were screened according to predetermined criteria. A total of 22 peer-reviewed publications were included in the final analysis. Studies were located in Australia and the western United States, with a single study in the Amazonian region of Brazil. The studies identified focused primarily on the impact of wildfire smoke exposure on COVID-19 infection and mortality, and the impact of exposure to both crises on mental health. The collective evidence shows that wildfire exposure within the context of the pandemic exacerbated COVID-19 infection and mortality as well as various adverse mental health effects. Additional research is needed in more diverse contexts and with individual-level data. Findings highlight the need for public health preparedness to anticipate overlapping, related crises and to advance climate change mitigation to protect public health.

https://doi.org/10.1088/2752-5309/acc680

The following article is Open access

Intervention studies to reduce the impact of climate change on health in rural communities in the United States: a systematic review

Daniel J Smith et al 2023 Environ. Res.: Health 1 032001

Open abstract

View article, Intervention studies to reduce the impact of climate change on health in rural communities in the United States: a systematic review

PDF, Intervention studies to reduce the impact of climate change on health in rural communities in the United States: a systematic review

Climate change, the greatest public health threat of the 21st century, will uniquely affect rural areas that are geographically isolated and experience greater health inequities. This systematic review describes and evaluates interventions to lessen the effects of climate change on human health in the rural United States, including interventions on air pollution, vector ecology, water quality, severe weather, extreme heat, allergens, and water and food supply. Searches were constructed based on the eight domains of the Centers for Disease Control and Prevention (CDC) Framework "Impact of Climate Change on Human Health." Searches were conducted in EBSCO Environment Complete, EBSCO GreenFILE, Embase.com, MEDLINE via PubMed, and Web of Science. Duplicate citations were removed, abstracts were screened for initial inclusion, and full texts were screened for final inclusion. Pertinent data were extracted and synthesized across the eight domains. Article quality was assessed using the Mixed Methods Appraisal Tool. Of 8471 studies screened, 297 were identified for full text review, and a total 49 studies were included in this review. Across the domains, 34 unique interventions addressed health outcomes due to air pollution (n = 8), changes in vector ecology (n = 6), water quality (n = 5), severe weather (n = 3), extreme heat (n = 2) increasing allergens (n = 1), water and food supply (n = 1), and across multiple CDC domains (n = 8). Participatory action research methodology was commonly used and strived to mobilize/empower communities to tackle climate change. Our review identified three randomized controlled trials, with two of these three published in the last five years. While original research on the impact of climate change on health has increased in the past decade, randomized control trials may not be ethical, cost effective, or feasible. There is a need for time-efficient and high-quality scholarship that investigates intervention efficacy and effectiveness for reducing health impacts of climate change upon rural populations.

https://doi.org/10.1088/2752-5309/acbbe6

The following article is Open access

Community-based participatory research on the impact of greenspace on violent crime

Mardelle McCuskey Shepley et al 2023 Environ. Res.: Health 1 022001

Open abstract

View article, Community-based participatory research on the impact of greenspace on violent crime

PDF, Community-based participatory research on the impact of greenspace on violent crime

Background. The positive impact of greenspace on human health has been well documented, including several literature reviews and meta-analyses that have examined the broad benefits of nature connections. Researchers have also examined the relationship between nature and crime reduction and identified potential mechanisms underlying this outcome, such as the physiological impact of nature, lowered temperatures due to a reduction in the heat island effect, and places for community interaction. However, a critical shortcoming of this study is the lack of deep community involvement in the research process. Community-based participatory research (CBPR) is critical to ensuring that the findings are meaningful to communities and translatable. This study expands on recent literature reviews on greenspace outcomes by focusing on community-engaged research (CER). By gathering and summarizing studies on this topic, we address two subjects: (a) strategies that can be used to improve community engagement, and (b) environmental factors that impact community outcomes in greenspace settings. Methods. To explore these issues, we used a modified version of Arksey and O'Malley's framework for a structured literature review, employing the Web of Science, EbscoHost, Scopus, ProQuest Global, and Google Scholar databases. Results. We retrieved 772 publications using permutations of keywords related to violent crime, greenspaces, and CBPR. After eliminating duplicates, the reviewers worked in parallel to evaluate 700 titles and abstracts and identified 51 potentially relevant papers, ten of which met the requirements for inclusion in this analysis. Discussion. Based on the studies explored in this literature review, we identified the following strategies for improving CER: building partnerships, facilitating power-sharing, utilizing community-specific indicators of success, embracing perspectives of communities of color, and empowering community researchers. In the sample of studies described here, the factors contributing to the relationship between greenspace and violent crime were maintenance, activity programming, green interventions, and community involvement.

https://doi.org/10.1088/2752-5309/aca2d2

Accepted manuscripts

Open all abstracts, in this tab

The following article is Open access

Toxic air pollution and concentrated social deprivation are associated with low birthweight and preterm birth in Louisiana

Terrell et al 

Open abstract

View accepted manuscript, Toxic air pollution and concentrated social deprivation are associated with low birthweight and preterm birth in Louisiana

PDF, Toxic air pollution and concentrated social deprivation are associated with low birthweight and preterm birth in Louisiana

Previous studies indicate that pollution exposure can increase risks of adverse birth outcomes, but Black communities are underrepresented in this research, and the potential moderating role of neighborhood context has not been explored. These issues are especially relevant in Louisiana, which has a high proportion of Black residents, an entrenched history of structural racism, the most pounds of toxic industrial emissions annually, and among the nation's highest rates of low birthweight (LBW), preterm birth (PTB), and infant mortality. We investigated whether air pollution and social polarization by race and income (measured via the index of concentration at the extremes [ICE]) were associated with LBW and PTB among Louisiana census tracts (n = 1,101) using spatial lag models. Data sources included 2011-2020 birth records, U.S. Census Bureau 2017 demographic data, and 2017 Respiratory Hazard (RH) from the U.S. Environmental Protection Agency. Both RH and ICE were associated with LBW (z = 4.4, P < 0.0001; z = -27.0, P < 0.0001) and PTB (z = 2.3, P = 0.019; z = -16.7, P < 0.0001), with no interaction. Severely polluted tracts had 25% higher and 36% higher risks of LBW and PTB, respectively, versus unpolluted tracts. On average, 2,166 low birthweight and 3,583 preterm births annually were attributable to pollution exposure. Tracts with concentrated social deprivation (i.e. low ICE scores) had 53% higher and 34% higher risks of LBW and PTB, respectively, versus intermediate or mixed tracts. On average, 1,171 low birthweight and 1,739 preterm births annually were attributable to concentrated deprivation. Our ecological study found that a majority of adverse birth outcomes in Louisiana (i.e. 67% of LBW and PTB combined) are linked to air pollution exposure or disadvantage resulting from social polarization. These findings can inform research, policy, and advocacy to improve health equity in marginalized communities.

https://doi.org/10.1088/2752-5309/ad3084

The following article is Open access

Trends in air toxics cancer risk in Southern California, 1998-2018

Maestas et al 

Open abstract

View accepted manuscript, Trends in air toxics cancer risk in Southern California, 1998-2018

PDF, Trends in air toxics cancer risk in Southern California, 1998-2018

Air toxics are an important category of air pollutants that are known to cause adverse health effects, including increased cancer risk. Regulatory efforts at federal, state, and local levels have aimed to decrease air toxics emissions over the past several decades. This study evaluated trends in air toxics cancer risks in Southern California using data from 1998 to 2018. We estimated air toxics cancer risk for each of four iterations of the South Coast Air Quality Management District's Multiple Air Toxics Exposure Study, which included at least one year of measurements at 10 stations and air toxics modeling for each iteration. Cancer risks were calculated using the measured and modeled air toxics concentrations averaged over a one to two year period and multiplied by the corresponding cancer potency factor and combined exposure factor that accounted for multiple exposure pathways and children's increased sensitivity to the health effects of air pollution. We examined temporal trends in overall air toxics cancer risks and evaluated changes in the air toxics species that contributed most to cancer risk in the region. Both measurement and modeling results show that air toxics cancer risk in Southern California decreased by more than 80% between 1998 and 2018, including a decrease of about 50% from 2012 to 2018. Diesel particulate matter was the main risk driver, followed by benzene, 1,3-butadiene, and formaldehyde. We found that more densely populated communities showed larger decreases than sparsely populated areas. The substantial decrease in air toxics levels over this 20-year period points to the success of air pollution policies aimed at addressing air toxics emissions and can inform future policy efforts to further reduce air toxics health impacts.

https://doi.org/10.1088/2752-5309/ad2f09

Trending

Trending on Altmetric

Journal links

Submit an article

About the journal

Editorial Board

Author guidelines

Review for this journal

Publication charges

Journal collections

Contact us

Environmental Publications

Environmental Research Communications

Environmental Research Letters

Environmental Research: Climate

Environmental Research: Ecology

Environmental Research: Energy

Environmental Research: Food Systems

Environmental Research: Health

Environmental Research: Infrastructure and Sustainability

Journal information

2022-present

Environmental Research: Health

doi: 10.1088/issn.2752-5309

Online ISSN: 2752-5309

IOPscience

Journals

Books

IOP Conference Series

About IOPscience

Contact Us

Developing countries access

IOP Publishing open

access policy

Accessibility

IOP Publishing

Copyright 2024 IOP Publishing

Terms and Conditions

Disclaimer

Privacy

and Cookie Policy

Publishing Support

Authors

Reviewers

Conference

Organisers

This site uses cookies. By continuing to use this

site you agree to our use of cookies.

IOP Publishing Twitter page

IOP Publishing Facebook page

IOP Publishing LinkedIn page

IOP Publishing Youtube page

IOP Publishing WeChat QR code

IOP Publishing Weibo page

The enigmatic ERH protein: its role in cell cycle, RNA splicing and cancer - PubMed

The enigmatic ERH protein: its role in cell cycle, RNA splicing and cancer - PubMed

This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features!

Clipboard, Search History, and several other advanced features are temporarily unavailable.

Skip to main page content

An official website of the United States government

Here's how you know

The .gov means it’s official.

Federal government websites often end in .gov or .mil. Before

sharing sensitive information, make sure you’re on a federal

government site.

The site is secure.

The https:// ensures that you are connecting to the

official website and that any information you provide is encrypted

and transmitted securely.

Log in

Show account info

Close

Account

Logged in as:

username

Dashboard

Publications

Account settings

Log out

Access keys

NCBI Homepage

MyNCBI Homepage

Main Content

Main Navigation

Search:

Search

Advanced

Clipboard

User Guide

Save

Email

Send to

Clipboard

My BibliographyCollectionsCitation manager

Display options

Display options

Format

Abstract

PubMed

PMID

Save citation to file

Format:

Summary (text)

PubMed

PMID

Abstract (text)

CSV

Create file

Cancel

Email citation

Subject:

1 selected item: 24078386 - PubMed

To:

From:

Format:

Summary

Summary (text)

Abstract

Abstract (text)

MeSH and other data

Send email

Cancel

Add to Collections

Create a new collection

Add to an existing collection

Name your collection:

Name must be less than 100 characters

Choose a collection:

Unable to load your collection due to an error

Please try again

Add

Cancel

Add to My Bibliography

My Bibliography

Unable to load your delegates due to an error

Please try again

Add

Cancel

Your saved search

Name of saved search:

Search terms:

Test search terms

Would you like email updates of new search results?

Saved Search Alert Radio Buttons

Yes

No

Email:

(change)

Frequency:

Monthly

Weekly

Daily

Which day?

The first Sunday

The first Monday

The first Tuesday

The first Wednesday

The first Thursday

The first Friday

The first Saturday

The first day

The first weekday

Which day?

Sunday

Monday

Tuesday

Wednesday

Thursday

Friday

Saturday

Report format:

Summary

Summary (text)

Abstract

Abstract (text)

PubMed

Send at most:

1 item

5 items

10 items

20 items

50 items

100 items

200 items

Send even when there aren't any new results

Optional text in email:

Save

Cancel

Create a file for external citation management software

Create file

Cancel

Your RSS Feed

Name of RSS Feed:

Number of items displayed:

5

10

15

20

50

100

Create RSS

Cancel

RSS Link

Copy

Full text links

Silverchair Information Systems

Free PMC article

Full text links

ActionsCiteCollectionsAdd to CollectionsCreate a new collectionAdd to an existing collection

Name your collection:

Name must be less than 100 characters

Choose a collection:

Unable to load your collection due to an errorPlease try again

Add

Cancel

Display options

Display options

Format

AbstractPubMedPMID

Share

Permalink

Copy

Page navigation

Title & authors

Abstract

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Title & authors

Abstract

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Review

Protein Cell

Actions

Search in PubMed

Search in NLM Catalog

Add to Search

. 2013 Nov;4(11):807-12.

doi: 10.1007/s13238-013-3056-3.

The enigmatic ERH protein: its role in cell cycle, RNA splicing and cancer

Meng-Tzu Weng, Ji Luo

PMID:

24078386

PMCID:

PMC4875447

DOI:

10.1007/s13238-013-3056-3

Free PMC article

Item in Clipboard

Review

The enigmatic ERH protein: its role in cell cycle, RNA splicing and cancer

Meng-Tzu Weng et al.

Protein Cell.

2013 Nov.

Free PMC article

Show details

Display options

Display options

Format

Abstract

PubMed

PMID

Protein Cell

Actions

Search in PubMed

Search in NLM Catalog

Add to Search

. 2013 Nov;4(11):807-12.

doi: 10.1007/s13238-013-3056-3.

Authors

Meng-Tzu Weng, Ji Luo

PMID:

24078386

PMCID:

PMC4875447

DOI:

10.1007/s13238-013-3056-3

Item in Clipboard

Full text links

CiteDisplay options

Display options

Format

AbstractPubMedPMID

Abstract

Enhancer of rudimentary homolog (ERH) is a small, highly conserved protein among eukaryotes. Since its discovery nearly 20 years ago, its molecular function has remained enigmatic. It has been implicated to play a role in transcriptional regulation and in cell cycle. We recently showed that ERH binds to the Sm complex and is required for the mRNA splicing of the mitotic motor protein CENP-E. Furthermore, cancer cells driven by mutations in the KRAS oncogene are particularly sensitive to RNAi-mediated suppression of ERH function, and ERH expression is inversely correlated with survival in colorectal cancer patients whose tumors harbor KRAS mutation. These recent findings indicate that ERH plays an important role in cell cycle through its mRNA splicing activity and is critically required for genomic stability and cancer cell survival.

PubMed Disclaimer

Similar articles

Thirty Years with ERH: An mRNA Splicing and Mitosis Factor Only or Rather a Novel Genome Integrity Protector?

Kozlowski P.

Kozlowski P.

Cells. 2023 Oct 13;12(20):2449. doi: 10.3390/cells12202449.

Cells. 2023.

PMID: 37887293

Free PMC article.

Review.

ERH Gene and Its Role in Cancer Cells.

Pang K, Li ML, Hao L, Shi ZD, Feng H, Chen B, Ma YY, Xu H, Pan D, Chen ZS, Han CH.

Pang K, et al.

Front Oncol. 2022 May 23;12:900496. doi: 10.3389/fonc.2022.900496. eCollection 2022.

Front Oncol. 2022.

PMID: 35677162

Free PMC article.

Review.

Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells.

Weng MT, Lee JH, Wei SC, Li Q, Shahamatdar S, Hsu D, Schetter AJ, Swatkoski S, Mannan P, Garfield S, Gucek M, Kim MK, Annunziata CM, Creighton CJ, Emanuele MJ, Harris CC, Sheu JC, Giaccone G, Luo J.

Weng MT, et al.

Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):E3659-67. doi: 10.1073/pnas.1207673110. Epub 2012 Dec 10.

Proc Natl Acad Sci U S A. 2012.

PMID: 23236152

Free PMC article.

Structure of the conserved transcriptional repressor enhancer of rudimentary homolog.

Wan C, Tempel W, Liu ZJ, Wang BC, Rose RB.

Wan C, et al.

Biochemistry. 2005 Apr 5;44(13):5017-23. doi: 10.1021/bi047785w.

Biochemistry. 2005.

PMID: 15794639

A 1.55 A resolution X-ray crystal structure of HEF2/ERH and insights into its transcriptional and cell-cycle interaction networks.

Jin T, Guo F, Serebriiskii IG, Howard A, Zhang YZ.

Jin T, et al.

Proteins. 2007 Aug 1;68(2):427-37. doi: 10.1002/prot.21343.

Proteins. 2007.

PMID: 17444515

See all similar articles

Cited by

Upregulated enhancer of rudimentary homolog promotes epithelial‑mesenchymal transition and cancer cell migration in lung adenocarcinoma.

Tsai YM, Wu KL, Huang YC, Wu YY, Chang CY, Chang YY, Chiang HH, Liu LX, Hung JY.

Tsai YM, et al.

Mol Med Rep. 2024 Jan;29(1):9. doi: 10.3892/mmr.2023.13132. Epub 2023 Nov 24.

Mol Med Rep. 2024.

PMID: 37997813

Free PMC article.

Thirty Years with ERH: An mRNA Splicing and Mitosis Factor Only or Rather a Novel Genome Integrity Protector?

Kozlowski P.

Kozlowski P.

Cells. 2023 Oct 13;12(20):2449. doi: 10.3390/cells12202449.

Cells. 2023.

PMID: 37887293

Free PMC article.

Review.

Identification of key pathways, genes and immune cell infiltration in hypoxia of high-altitude acclimatization via meta-analysis and integrated bioinformatics analysis.

Li Q, Xu Z, Fang F, Shen Y, Lei H, Shen X.

Li Q, et al.

Front Genet. 2023 Mar 24;14:1055372. doi: 10.3389/fgene.2023.1055372. eCollection 2023.

Front Genet. 2023.

PMID: 37035734

Free PMC article.

ERH Gene and Its Role in Cancer Cells.

Pang K, Li ML, Hao L, Shi ZD, Feng H, Chen B, Ma YY, Xu H, Pan D, Chen ZS, Han CH.

Pang K, et al.

Front Oncol. 2022 May 23;12:900496. doi: 10.3389/fonc.2022.900496. eCollection 2022.

Front Oncol. 2022.

PMID: 35677162

Free PMC article.

Review.

Oncogenic dependency on STAT3 serine phosphorylation in KRAS mutant lung cancer.

Alhayyani S, McLeod L, West AC, Balic JJ, Hodges C, Yu L, Smith JA, Prodanovic Z, Bozinovski S, Kumar B, Ruwanpura SM, Saad MI, Jenkins BJ.

Alhayyani S, et al.

Oncogene. 2022 Feb;41(6):809-823. doi: 10.1038/s41388-021-02134-4. Epub 2021 Dec 3.

Oncogene. 2022.

PMID: 34857889

See all "Cited by" articles

References

Amente S, Napolitano G, Licciardo P, Monti M, Pucci P, Lania L, Majello B. Identification of proteins interacting with the RNAPII FCP1 phosphatase: FCP1 forms a complex with arginine methyltransferase PRMT5 and it is a substrate for PRMT5-mediated methylation. FEBS Lett. 2005;579:683–689. doi: 10.1016/j.febslet.2004.12.045.

-

DOI

-

PubMed

Arai R, Kukimoto-Niino M, Uda-Tochio H, Morita S, Uchikubo-Kamo T, Akasaka R, Etou Y, Hayashizaki Y, Kigawa T, Terada T, et al. Crystal structure of an enhancer of rudimentary homolog (ERH) at 2.1 Angstroms resolution. Protein Sci. 2005;14:1888–1893. doi: 10.1110/ps.051484505.

-

DOI

-

PMC

-

PubMed

Balaji S, Aravind L. The RAGNYA fold: a novel fold with multiple topological variants found in functionally diverse nucleic acid, nucleotide and peptide-binding proteins. Nucleic Acids Res. 2007;35:5658–5671. doi: 10.1093/nar/gkm558.

-

DOI

-

PMC

-

PubMed

Battle DJ, Kasim M, Yong J, Lotti F, Lau C-K, Mouaikel J, Zhang Z, Han K, Wan L, Dreyfuss G. The SMN complex: an assembly machine for RNPs. Cold Spring Harb. Symp. Quant Biol. 2006;71:313–320. doi: 10.1101/sqb.2006.71.001.

-

DOI

-

PubMed

Beggs JD. Lsm proteins and RNA processing. Biochem Soc Trans. 2005;33:433–438. doi: 10.1042/BST0330433.

-

DOI

-

PubMed

Show all 35 references

Publication types

Research Support, N.I.H., Intramural

Actions

Search in PubMed

Search in MeSH

Add to Search

Research Support, Non-U.S. Gov't

Actions

Search in PubMed

Search in MeSH

Add to Search

Review

Actions

Search in PubMed

Search in MeSH

Add to Search

MeSH terms

Amino Acid Sequence

Actions

Search in PubMed

Search in MeSH

Add to Search

Animals

Actions

Search in PubMed

Search in MeSH

Add to Search

Cell Cycle*

Actions

Search in PubMed

Search in MeSH

Add to Search

Evolution, Molecular

Actions

Search in PubMed

Search in MeSH

Add to Search

Humans

Actions

Search in PubMed

Search in MeSH

Add to Search

Molecular Sequence Data

Actions

Search in PubMed

Search in MeSH

Add to Search

Neoplasms / metabolism*

Actions

Search in PubMed

Search in MeSH

Add to Search

RNA Splicing*

Actions

Search in PubMed

Search in MeSH

Add to Search

Transcription Factors / chemistry

Actions

Search in PubMed

Search in MeSH

Add to Search

Transcription Factors / metabolism*

Actions

Search in PubMed

Search in MeSH

Add to Search

Transcription, Genetic

Actions

Search in PubMed

Search in MeSH

Add to Search

Substances

Transcription Factors

Actions

Search in PubMed

Search in MeSH

Add to Search

Related information

Gene

Gene (GeneRIF)

Nucleotide (RefSeq)

Protein (RefSeq)

Grants and funding

Intramural NIH HHS/United States

LinkOut - more resources

Full Text Sources

Europe PubMed Central

PubMed Central

Silverchair Information Systems

Springer

Other Literature Sources

The Lens - Patent Citations

scite Smart Citations

Miscellaneous

NCI CPTAC Assay Portal

Full text links

[x]

Silverchair Information Systems

Free PMC article

[x]

Cite

Copy

Download .nbib

.nbib

Format:

AMA

APA

MLA

NLM

Send To

Clipboard

Email

Save

My Bibliography

Collections

Citation Manager

[x]

NCBI Literature Resources

MeSH

PMC

Bookshelf

Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

Follow NCBI

Twitter

Facebook

LinkedIn

GitHub

Connect with NLM

Twitter

SM-Facebook

SM-Youtube

National Library of Medicine

8600 Rockville Pike

Bethesda, MD 20894

Web Policies

FOIA

HHS Vulnerability Disclosure

Help

Accessibility

Careers

NLM

NIH

HHS

USA.gov

A conserved dimer interface connects ERH and YTH family proteins to promote gene silencing | Nature Communications

A conserved dimer interface connects ERH and YTH family proteins to promote gene silencing | Nature Communications

Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain

the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in

Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles

and JavaScript.

Advertisement

View all journals

Search

Log in

Explore content

About the journal

Publish with us

Sign up for alerts

RSS feed

nature

nature communications

articles

article

A conserved dimer interface connects ERH and YTH family proteins to promote gene silencing

Download PDF

Download PDF

Article

Open access

Published: 16 January 2019

A conserved dimer interface connects ERH and YTH family proteins to promote gene silencing

Guodong Xie1 na1, Tommy V. Vo2 na1, Gobi Thillainadesan2, Sahana Holla2, Beibei Zhang1, Yiyang Jiang1, Mengqi Lv1, Zheng Xu1, Chongyuan Wang1, Vanivilasini Balachandran2, Yunyu Shi1, Fudong Li1 & …Shiv I. S. Grewal 

ORCID: orcid.org/0000-0002-4552-92612 Show authors

Nature Communications

volume 10, Article number: 251 (2019)

Cite this article

4651 Accesses

29 Citations

14 Altmetric

Metrics details

Subjects

ChromatinGene silencingStructural biologyTranscription

AbstractGene regulatory mechanisms rely on a complex network of RNA processing factors to prevent untimely gene expression. In fission yeast, the highly conserved ortholog of human ERH, called Erh1, interacts with the YTH family RNA binding protein Mmi1 to form the Erh1-Mmi1 complex (EMC) implicated in gametogenic gene silencing. However, the structural basis of EMC assembly and its functions are poorly understood. Here, we present the co-crystal structure of the EMC that consists of Erh1 homodimers interacting with Mmi1 in a 2:2 stoichiometry via a conserved molecular interface. Structure-guided mutation of the Mmi1Trp112 residue, which is required for Erh1 binding, causes defects in facultative heterochromatin assembly and gene silencing while leaving Mmi1-mediated transcription termination intact. Indeed, EMC targets masked in mmi1∆ due to termination defects are revealed in mmi1W112A. Our study delineates EMC requirements in gene silencing and identifies an ERH interface required for interaction with an RNA binding protein.

Similar content being viewed by others

Enhancer selectivity in space and time: from enhancer–promoter interactions to promoter activation

Article

27 February 2024

Jin H. Yang & Anders S. Hansen

Nuclear export of circular RNA

Article

14 February 2024

Linh H. Ngo, Andrew G. Bert, … Vihandha O. Wickramasinghe

Nucleosome-bound NR5A2 structure reveals pioneer factor mechanism by DNA minor groove anchor competition

Article

Open access

26 February 2024

Wataru Kobayashi, Anna H. Sappler, … Kikuë Tachibana

IntroductionGene expression is tightly regulated to ensure accurate translation of genetic information in response to developmental and environmental signals. A variety of gene regulatory mechanisms generate diverse expression patterns reflecting the cell type or specific developmental stage1,2. In addition to transcriptional gene control3,4,5, factors acting at the level of posttranscriptional processing have emerged as critical players in defining gene expression profiles and preventing ectopic expression of genetic information6,7,8,9. Indeed, untimely gene expression is a major cause of diseases including cancer10,11. Despite major advances in our understanding of conserved gene regulatory pathways, mechanisms underlying developmental or environmental control of gene expression remain poorly understoodThe fission yeast Schizosaccharomyces pombe contains highly conserved RNA processing and chromatin-modifying activities, thus providing an excellent model system for exploring gene regulatory mechanisms4. One such regulatory mechanism controls major developmental changes that occur in response to nutrient starvation. In cells starved of nitrogen, the switch from the mitotic to the meiotic cell cycle requires the coordinated activation of hundreds of gametogenic genes involved in meiosis and sexual differentiation12. During the mitotic cell cycle, silencing of these genes9 requires a highly conserved protein named Enhancer of rudimentary homolog 1 (Erh1)13,14,15 belonging to the ERH protein family implicated in various nuclear processes16. Erh1 associates with nuclear RNA elimination factors, including MTREC (PAXT in mammals17), which is composed of the zinc-finger protein, Red1, and the Mtr4-like protein, Mtl1, as well as the CCR4-NOT complex that act together with other factors to facilitate RNA degradation by the 3′→5′ exonuclease Rrp6 and RNAi machinery15,18,19,20,21,22,23,24,25. Moreover, Erh1 and its interaction partners have been shown to mediate targeting of the histone 3 lysine-9 (H3K9) methyltransferase Clr4 (a homolog of mammalian Suv39h) to assemble facultative heterochromatin at meiotic genes26,27,28. This provides an additional level of gene silencing that offers protection from the deleterious effects of improper meiotic gene expression during the mitotic cell cycle.Many gametogenic gene transcripts silenced by Erh1 contain a determinant of selective removal (DSR) element that is recognized by the YTH-domain of the RNA binding protein Mmi118,29,30,31,32,33. Recent work has revealed that Mmi1 interacts with Erh1 to form a complex, called EMC14, and loss of Mmi1 affects recruitment of Erh1 and its associated RNA processing activities to target transcripts14,27. Despite these advances, the structural features of EMC and the functional significance of complex formation for silencing gametogenic genes and assembling facultative heterochromatin has remained enigmatic. Moreover, it remains unclear whether Mmi1 association with Erh1 is critical for the diverse functions attributed to Mmi1, including its recently described role in non-canonical transcription termination of meiotic mRNAs and regulatory long non-coding RNAs (lncRNAs)34,35,36.Here, we present the co-crystal structure of Erh1 in complex with the amino-terminal domain of Mmi1. Our structure reveals that Mmi1 binds homodimers of Erh1 in a 2:2 stoichiometry, via a conserved molecular interface characteristic of ERH family proteins. Structure-guided mutational analysis shows that the Mmi1-Erh1 interaction is essential for facultative heterochromatin assembly and for silencing of gametogenic genes. Interestingly, we discover that an important function of Mmi1 in promoting non-canonical transcription termination at meiotic genes, and in preventing lncRNAs from invading and repressing adjacent genes, is not dependent upon its association with Erh1. Therefore, we not only reveal a distinct requirement for EMC among the various functional roles attributed to Mmi1 but also discover that the structural basis for EMC assembly involves a highly conserved ERH dimer interface.ResultsErh1 interacts with the amino-terminal domain of Mmi1Erh1 and Mmi1 form a protein complex called EMC14, but the nature of the interaction between these factors had not yet been characterized. To study this, we set out to determine the precise domain in Mmi1 that binds to Erh1. Mmi1 is a 488 amino acid protein that consists of a carboxy-terminal YTH domain and a largely unstructured amino-terminus (Fig. 1a). The carboxy-terminal YTH domain is known to bind to DSR motif-containing RNA18,29,30,31,32,33. However, we detected no interaction between the purified GST-tagged YTH domain of Mmi1 and His-tagged Erh1 protein (Fig. 1b).Fig. 1Mmi1 interacts with Erh1 in a 2:2 stoichiometry. a Shown is a schematic representation of the domain architecture of Mmi1. The disorder score from DISOPRED3 Server62 and the conservation score are shown below. The conservation score is generated by a Protein Residue Conservation Prediction Server63 from the sequence alignment of Mmi1 orthologues from S. pombe, S. cryophilus, S. octosporus, and S. japonicus. b–d Interactions of GST tagged Mmi1 peptides (GST-Mmi1) with Erh1 visualized by Coomassie blue staining. The indicated GST-Mmi1 fusion proteins or GST alone were incubated with Erh1. The complexes were collected with glutathione-agarose resin and bound proteins were eluted and then subjected to SDS-PAGE. GST or GST-Mmi1 fusion proteins without Erh1 are shown as a negative control. Source data are provided as a Source Data file. e The raw ITC titration data of Erh1 with SUMO tagged Mmi195–122 and its fitting curve are shown. KD dissociation constant, DP differential power, N binding stoichiometry, ΔH binding enthalpy. f ITC fitting curves of Erh1 using SUMO tagged Mmi195–122 (magenta), Mmi1106–122 (blue) and Mmi195–111 (green) are shown. g Size-exclusion analysis of Erh1 (magenta) and Erh1-Mmi195–122 (blue). Marker sizes are 62.9 KDa (Albumin), 46.7 KDa (Ovalbumin), 20.3 KDa (Chymotrypsinogen), 14.6 KDa (Ribonuclease A). Also shown are theoretical monomer sizes (kDa) of Erh1 protein and Mmi195–122 peptideFull size imageWe next tested the amino-terminal portion of Mmi1 for its ability to bind to Erh1. We were unable to obtain soluble fusion proteins encoding the GST-tagged amino-terminal (residues 1–321) region of Mmi1. Upon closer inspection, we noticed that Mmi1 residues 1–122 are highly conserved, especially within two short segments (residues 64–75 and 95–122) (Fig. 1a and Supplementary Fig. 1). We found that the purified GST-tagged Mmi11–122 amino-terminal fragment bound efficiently to Erh1 (Fig. 1b, c), and that an even shorter fragment containing Mmi1 residues 95–122 was sufficient for interaction (Fig. 1c, d). To confirm this finding, we performed isothermal titration calorimetry (ITC). Remarkably, Mmi195–122 bound to Erh1 with a dissociation constant (KD) of 0.83 ± 0.19 μM and an N value of ~1 (0.90) (Fig. 1e and Supplementary Table 1). Moreover, the further truncated Mmi1106–122 fragment showed decreased binding to Erh1, while the Mmi195–111 peptide did not bind at all (Fig. 1d, f). Therefore, we conclude that Mmi195–122 includes the Erh1-interacting domain (EID) that is necessary and sufficient to mediate EMC formation.EMC consists of homodimers of Erh1 bound to Mmi1Next, we assessed the stoichiometry of Erh1 and Erh1-Mmi195–122 complexes by analytical size-exclusion chromatography (SEC) using a calibrated Superdex75 10/300 GL column (GE Healthcare). Erh1 eluted as a single peak at 11.41 mL, corresponding to an apparent molecular weight (MW) of 26 kDa. With a predicted molecular weight (MW) of ~13.2 kDa, this elution profile likely represents Erh1 homodimers (Fig. 1g). This is consistent with previous reports showing that human ERH protein exists as a dimer in solution37.We next purified SUMO-tagged Mmi195–122 and incubated it with Erh1, followed by removal of the SUMO tag by ULP1 enzyme. The association of Erh1 with Mmi195–122 resulted in a shift of about 0.25 mL in elution volume to ~11.16 mL, with a calculated MW of 33 kDa. This result is in accordance with the expected MW of two Erh1 molecules forming a complex with two Mmi195–122 peptides (Fig. 1g), which was further confirmed by the N value of the ITC result (Fig. 1e). Together, these results suggest that binding of the Mmi195–122 domain to Erh1 does not disrupt the Erh1 homodimer interface and that EMC forms in a 2:2 Erh1-Mmi1 stoichiometry.Co-crystal structure of EMCWe determined the structure of EMC by crystallizing Erh1 in complex with Mmi195–122. We used a (Gly-Ser-Ser)5 linker to fuse Erh1 and Mmi195–122 in tandem. The co-crystal structure was resolved to 2.7 Å resolution by molecular replacement. We refined the structure to an Rwork of 20.67%, an Rfree of 24.09% and satisfactory stereochemistry (Supplementary Table 2). Consistent with the 2:2 stoichiometry model based on the results from the SEC experiments, the co-crystal structure revealed that Erh1 forms a homodimer, with two Mmi1 subunits bound on the surface of the Erh1 homodimer (Fig. 2a, b). The final model includes residues 6–45 and 55–101 of Erh1 and residues 96–119 of Mmi1 without any linker sequence (the 2Fo-Fc electron density map for residues 96–119 of Mmi1 is shown in Supplementary Fig. 2).Fig. 2Structure of Erh1 in complex with Mmi195–122 peptide. a Ribbon representations of Erh1 bound to Mmi195–122 peptide. One monomer of the Erh1 homodimer is colored in aquamarine, while the other is colored in wheat. The two bound Mmi195–122 peptides are colored in magenta. b The two Mmi195–122 peptides are represented as sticks on the molecular face of the Erh1 homodimer. Red and blue colors denote negative and positive surface charge, respectively. c Ribbon representation of the interface of the Erh1 dimer. The residues at the dimer interface are shown as sticks. The hydrogen bonds formed at the dimer interface are depicted as black dashed linesFull size imageOverall, the Erh1 monomer adopted a typical ERH fold, characterized by a four-stranded antiparallel β-sheet (β1–β4) and three α-helixes (α1–α3), with the α-helixes on one face of the sheet (Fig. 2a). The outside faces of the β-sheets of two monomers constituted the homodimer interface and formed a pseudo-β-barrel, burying about 1000 Å2 of solvent-exposed area (Fig. 2a). At the dimer interface, hydrophobic interactions formed among the side chains of Erh1 residues Ile11, Leu13, Trp25, Leu72, Tyr81, and Pro83; two main-chain hydrogen bonds between the carbonyl oxygen and amide nitrogen atoms of Tyr81 on strand 4 of each monomer; side-chain hydrogen bonds between Arg23 and Asp27 of each monomer (Fig. 2c). Interestingly, the residues of the dimer interface are significantly conserved among divergent eukaryotic species (Fig. 3a), suggesting that dimer formation is essential for Erh1 function.Fig. 3Molecular interface between Erh1 and Mmi195–122. a Sequence alignment of S. pombe Erh1 and the enhancer of rudimentary homolog (ERH) proteins from H. sapiens (Human), C. elegans (Worm), and D. melanogaster (Fly). The alignment was generated by ESPript3 with CLUSTALW. The secondary structures of Erh1, as determined by DSSP, are shown above the sequences. The conserved residues at the ERH dimer interface are emphasized by up-pointing triangles below the sequences. The key residues for Mmi1Trp1112 interaction are emphasized by down-pointing triangles above the sequences. Aligned amino acids in red share similar biophysical properties, those in white with red highlight are perfectly conserved, and blue boxes denote conserved clusters of amino acids. Black arrows denote hydrophobic residues, blue arrows denote residues involved in hydrogen bond interaction. b Sequence alignment of Mmi195–122 of S. pombe and the corresponding regions from S. cryophilus, S. octosporus, and S. japonicus. The secondary structures are also shown above the sequences. c Interactions of MmiTrp112, α-helix H2, 310 helix H1, and N-terminal loop with Erh1 dimer. Erh1 (aquamarine and wheat) and Mmi195–122 (magenta) are shown as ribbons with selected side-chain and main-chain atoms as sticks. Hydrogen bonds are shown as black dashed lines. The Y97 and F99 subpanel shows the binding pocket for Mmi1Tyr97 and Mmi1Phe99; the Hydrogen bonding panel shows the hydrogen bonding network between Mmi1 and the Erh1 dimer; the H1 subpanel shows the interactions between the 310 helix H1 of Mmi1 EIM peptide and Erh1 dimer; the W112 subpanel shows the hydrophobic pocket of the Erh1 dimer for Mmi1Trp112 recognition; the H2 subpanel shows the interactions between the α-helix H2 Mmi1 of the EIM peptide and the Erh1 dimer. d GST pull-down assay showing the diminished interaction between the Mmi1W112A mutant and Erh1. Source data are provided as a Source Data file. e ITC fitting curves of Erh1 using SUMO tagged Mmi195–122 (magenta) and Mmi1W112A (blue) are shownFull size imageConsistent with our biochemical analyses, the structure showed two Mmi195–122 peptides bound on the surface of the Erh1 homodimer in a similar extended conformation, burying more than 2500 Å2 of the solvent-exposed area of Erh1 (Fig. 2a, b). Each Mmi1 peptide was bound across the β2 edge of the β-sheet of each Erh1 monomer, with the amino-terminal residues (Mmi1Lys96-Mmi1Cys103) located in the groove between α-helix α1 and the β-sheet, whereas the carboxy-terminal residues (Mmi1Thr104-Mmi1Arg119) were bound to the hydrophobic core of the dimer pseudo-β-barrel (Fig. 2a). Taken together, the co-crystal structure of Erh1-Mmi195–122 revealed that binding of Mmi1 to Erh1 occurs as a heterotetramer and involves an extensive set of inter- and intra-molecular interactions.Intra- and inter-molecular interactions stabilize EMCWhen bound to Erh1, the carboxy-terminal residues of the Mmi195–122 peptide (109SYEWPYFRSLR119) folded into two consecutive helices, consisting of a 310 helix (H1) and an α-helix (H2) (Figs. 2a, 3b). The two helices were connected via the Mmi1Trp112 residue. The Mmi1Trp112 aromatic ring stretched into a deep hydrophobic pocket formed by Erh1His9, Erh1Val70, Erh1Ile11, Erh1Leu13, and Erh1Trp25, with its Nε nitrogen forming a hydrogen bond with the side chain of Erh1Asp27 (Fig. 3c). Indeed, Mmi1Trp112 is crucial for EMC formation as substitution with alanine disrupted Mmi1-Erh1 interaction as confirmed by GST pull-down assay and ITC (Fig. 3d, e). Besides Mmi1Trp112, residues Mmi1Pro113-Mmi1Arg119 (113PYFRSLR119) formed the α-helix H2, from which several conserved hydrophobic side chains protruded and formed multiple van der Waals contacts with the dimer pseudo-β-barrel (Fig. 3b, c). Specifically, the side chains of Mmi1Pro113, Mmi1Tyr114, and Mmi1Phe115 interacted with the dimer interface formed by the side chains of Erh1Glu7, Erh1Tyr74, Erh1Arg79, Erh1Val70, and Erh1Pro83 (Fig. 3c). It is noteworthy that the hydrophobic residues involved in the dimer formation also contributed to the recognition of Mmi1Trp112 and the α-helix H2. The importance of the hydrophobic interactions between Mmi1 H2 and the Erh1 dimer was confirmed by mutational analysis. Mmi1Y114A and Mmi1F115A showed reduced affinities for Erh1 as revealed by ITC (Supplementary Table 1).Additional structures that contribute to EMC stability include the polypeptide chain 109SYE111 that formed a short 310 helix H1 (Fig. 3c). The amide nitrogen and side-chain hydroxyl oxygen atoms of Mmi1Ser109 formed bifurcated hydrogen bonds with the side chain of Erh1Asp68. Consequently, the side chains of Mmi1Tyr110 and Mmi1Asp111 bulged out with no direct contact with Erh1. The conformation may allow Mmi1Trp112 to point towards Erh1. Interestingly, the side chain of Mmi1Tyr110 interacted with Mmi1Arg119 via cation-π interactions. Furthermore, a hydrogen bond linked the carbonyl oxygen of Mmi1Tyr110 and the side chain of Mmi1Arg119. Confirming the importance of these interactions, the affinities of the Erh1D68A mutant for the Mmi195–122 peptide, and the Mmi1R119A mutant for Erh1, were reduced (Supplementary Table 1). We also observed that the H1 helix toward the amino-terminus, Mmi1 (96KYDFSRHCTDYGH108), adopted a long structural loop conformation featuring several turns, which was constrained by an intertwined network of both intra- and inter-molecular interactions. The inter-molecular interactions between Mmi1 and Erh1 contained both hydrophobic contacts and numerous direct hydrogen bonds. Most of the hydrophobic contacts involved Mmi1Tyr97 and Mmi1Phe99. The side chain of Mmi1Tyr97 was surrounded by a shallow channel flanked by Erh1Tyr42 and Erh1Phe62. In the neighboring channel, the side chain of Mmi1Phe99 was accommodated by Erh1Ile14, Erh1Tyr37, Erh1Val41, Erh1Phe62, and Erh1Ile66 (Fig. 3c). Consistent with these observations, Mmi1Y97A and Mmi1F99A mutants showed reduced affinities for Erh1 (Supplementary Table 1).Among the specific hydrogen bonds, most contacts involved Erh1Asp27 and Erh1Arg23 that also played a role in Erh1 dimer interactions. Across the β2 edge of the Erh1 monomer β-sheet, the carbonyl oxygen of Mmi1Cys103 and the amide nitrogen of Mmi1Asp105 formed hydrogen bonds with the main chain of Erh1Asp27. Additionally, the side chains of Erh1Asp27 and Erh1Arg23 also formed numerous hydrogen bonds with Mmi1, including with the side chains of Mmi1Trp112 and Mmi1Thr104, as well as the carbonyl oxygen of Mmi1Cys103 (Fig. 3c). Underscoring the importance of these Erh1 residues, substitution of Erh1Asp27 or Erh1Arg23 with alanine significantly reduced the binding affinity of Erh1 for Mmi195–122 (Supplementary Table 1). Furthermore, the side chain and the carbonyl oxygen of Erh1Tyr67 formed hydrogen bonds with the carbonyl oxygen of Mmi1Gly107 and the Nε2 group of Mmi1H108, respectively. Hydrogen bonds also formed between Mmi1Glu98 and Mmi1Asp105 and the side chains of Erh1Thr44 and Erh1Ser33, respectively (Fig. 3c). In addition to these inter-molecular interactions, there are several intra-molecular interactions that helped constrain the structural loop conformation of the Mmi1 peptide: two hydrogen bonds between the side chain of Mmi1Asp98 and the side chain of Mmi1Ser100; one hydrogen bond between the side chain of Mmi1Thr104 and the nitrogen atom of Mmi1Tyr106 (Fig. 3c). Overall, this complex network of interactions serves to stabilize the structure of Mmi1 and contributes to EMC formation.The Erh1-Mmi1 binding interface is conserved in human ERHWe next investigated whether the Erh1 dimer interface that interacts with Mmi1 shares features with human ERH. In addition to conservation of residues at the dimer interface (Fig. 3a), structural comparison of the Mmi1-bound Erh1 homodimer with the previously characterized human ERH homodimer (PDB ID:1WZ7) revealed significant similarities (with a r.m.s deviation of 0.98 Å over 135 Cα atoms) (Supplementary Fig. 3a). Moreover, the conformations of the residues at the dimer interface were perfectly conserved. The Erh1 binding pocket that mediates binding to Mmi1Trp112 was also nearly identical between S. pombe Erh1 and human ERH (Supplementary Fig. 3b, c). This high degree of structural conservation between evolutionarily distant ERH family proteins suggests that the dimer interface might be a conserved protein–protein interaction platform that facilitates binding of ERH family proteins to species-specific factors.The Erh1-Mmi1 interface is required for EMC function in vivoGuided by the results from our structural and biochemical analyses above, we created a mutant mmi1 allele to investigate the biological significance of EMC assembly (Supplementary Fig. 4a). We reasoned that an S. pombe strain expressing an mmi1W112A mutant allele, which should disrupt the Erh1-Mmi1 interface and prevent EMC assembly, would allow us to uncouple EMC functions from other roles specific to either Mmi1 or Erh1. The mutant MmiW112A protein was expressed at levels comparable to that of the WT Mmi1 (Fig. 4a and Source Data). However, replacing WT Mmi1 with Mmi1W112A drastically diminished the Erh1-Mmi1 interaction as determined by co-immunoprecipitation (Fig. 4b). This finding is consistent with the conclusion that Mmi1Trp112 is critical for EMC assembly in vivo.Fig. 4Mmi1W112A perturbs EMC functions in vivo. a Western blot analysis of FLAG-Mmi1 WT and FLAG-Mmi1W112A protein expression levels. Cdc2 serves as loading control. Also shown is a linear schematic of mmi1W112A mutant. Source data are provided as a Source Data file. b Coimmunoprecipitation of Erh1-GFP and FLAG-Mmi1 WT or FLAG-Mmi1W112A. Source data are provided as a Source Data file. c Spotting assays at 32, 37, or 18 °C on non-selective media. The mmi1-ts6 strain was included as a control for 37 °C growth. d Erh1 localization in WT or mmi1W112A cells. WT and mutant cells expressing Erh1-GFP were imaged using a DeltaVision Elite fluorescence microscope (Applied Precision, GE Healthcare). Scale bar (white) represents 5 μm. e Western blot analysis depicting Erh1 protein levels in wild-type or mmi1W112A cells. Ponceau S stain serves as a loading control. Source data are provided as a Source Data file. f ChIP-qPCR analyses of Erh1-GFP enrichment in WT and mmi1W112A cells at indicated loci. Fold enrichment values plotted were calculated relative to the control leu1 locus. Shown are mean±SD for two experimentsFull size imageWe next compared the phenotypes of mmi1W112A and erh1∆. Cells expressing the mutant protein showed no obvious growth defects at 32 °C and 37 °C (Fig. 4c). However, mmi1W112A cells displayed cold-sensitivity at 18 °C, similar to erh1∆ (Fig. 4c). We also tested whether mating and meiotic progression were affected by exposing WT and mutant colonies to iodine vapor38. When meiosis is induced, homothallic WT cells sporulate and form asci. The starch-like compound in the spore wall is stained with dark color when exposed to iodine vapor. Indeed, mmi1W112A cells showed decreased intensity of iodine staining and a reduced mating efficiency, in a manner similar to erh1∆ (Supplementary Fig. 4b). Thus, mmi1W112A mimics the defective mating and meiotic progression phenotypes displayed by cells lacking Erh1.We further explored whether Mmi1W112A affects the localization of Erh1. Erh1 forms nuclear foci that co-localize with RNA elimination factors including Mmi114. Indeed, Erh1 foci were not observed when GFP-tagged Erh1 (Erh1-GFP) was expressed in mmi1W112A mutant cells (Fig. 4d). This was not due to destabilization of Erh1, as comparable levels of Erh1-GFP were detected in WT and mmi1W112A (Fig. 4e). Furthermore, localization of Erh1 at EMC target loci was abolished in mmi1W112A (Fig. 4f). Taken together, these results suggest that EMC assembly is critical for Erh1 association with its target loci, and that the Mmi1W112A mutation specifically disrupts EMC assembly without affecting other essential function(s) of Mmi1.Erh1-Mmi1 interaction is required for H3K9me at islandsRNA-based mechanisms target Clr4 H3K9 methyltransferase to promote heterochromatin assembly39. In addition to constitutive heterochromatin domains at centromeres, telomeres, and the mating-type locus, discrete blocks of facultative heterochromatin islands are detected across the S. pombe genome40. Among these, the assembly of heterochromatin islands at meiotic genes requires RNA elimination machinery19,26,27,28. Indeed, cells lacking Mmi1, which binds to DSR-containing meiotic mRNAs, or Erh1 are defective in the assembly of meiotic heterochromatin islands14,19,26,27,28,34.We utilized the mmi1W112A to explore whether the Mmi1-Erh1 interaction, rather than the individual functions of these factors, is critical for facultative heterochromatin assembly. A comparison of the genome-wide distribution of H3K9me in mmi1W112A and WT cells revealed a dramatic reduction in H3K9me at many facultative heterochromatin islands in the mutant (Fig. 5a, b and Supplementary Fig. 5a, b). Defects in H3K9me in mmi1W112A occurred specifically at meiotic heterochromatin islands that also require Erh1 for heterochromatin assembly (Supplementary Table 3)14. H3K9me at Erh1-independent heterochromatin islands was not affected in mmi1W112A (Fig. 5c and Supplementary Fig. 5a, b). Moreover, H3K9me at constitutive heterochromatin domains, such as at pericentromeric regions and telomeres, was not affected in mmi1W112A or erh1∆ (Fig. 5a and Supplementary Fig. 5c). Conventional ChIP combined with real-time quantitative PCR (ChIP-qPCR) confirmed defects in H3K9me in mmi1W112A at Erh1-dependent islands associated with the meiotic genes ssm4 and mei4 (Supplementary Fig. 5d). Overall, these results suggest that the Erh1-Mmi1 interaction to form EMC is required for the assembly of facultative heterochromatin islands at meiotic genes.Fig. 5Mmi1W112A affects EMC-dependent facultative heterochromatin islands. a Genome-wide ChIP-seq profiles showing enrichment of histone H3 dimethylation (H3K9me2) in WT and mmi1W112A cells. Examples of several individual heterochromatin islands are indicated. b H3K9me2 enrichment ChIP-seq profiles of EMC-dependent islands. c H3K9me2 enrichment ChIP-seq profiles of EMC-independent islands. The color scheme used in all plots shown is WT (black), mmi1W112A (red), and erh1∆ (blue)Full size imageErh1-Mmi1 interaction is required for gene silencingIn addition to the assembly of heterochromatin islands, Mmi1 and Erh1 promote mRNA decay to prevent the untimely expression of gametogenic genes in vegetative cells14. Indeed, aberrant expression of meiotic genes is a major cause of chromosomal abnormalities associated with cancer and other diseases41. To investigate whether mmi1W112A affects any of the transcripts that are upregulated in mmi1∆ and/or erh1∆ cells, we compared the transcriptomes of WT and mutant cells using RNA-seq. The strains carried a non-functional truncated allele of mei4 that rescues lethality caused by the deletion of mmi118. Interestingly, the expression profiles of mmi1W112A and erh1∆ were strikingly similar (Fig. 6a). The increase in transcripts observed in mmi1W112A was comparable to that observed in erh1∆ (Fig. 6b). Of the 138 transcripts upregulated in either mmi1W112A or erh1∆ (≥2-fold), a major class of transcripts was derived from loci that showed increased expression during nitrogen starvation and meiotic cell cycle progression. These included DSR-containing meiotic mRNAs and various lncRNAs that are targeted for degradation by RNA elimination factors19,35,36. The observed upregulation of DSR-containing mRNAs derived from ssm4, rec8, spo5, and mcp5 in mmi1W112A was confirmed using real-time quantitative PCR (RT-qPCR) (Supplementary Fig. 6a). These results show that mmi1W112A phenocopies erh1∆ and support the idea that the binding of Erh1 to Mmi1 is a prerequisite for EMC-dependent mRNA decay and gene silencing.Fig. 6Mmi1W112A affects a subset of the Mmi1 regulon silenced by EMC. a Heatmap of genes upregulated by ≥2-fold in at least one mutant as compared to WT. Cluster 1 contains genes that are derepressed in mmi1∆, mmi1W112A, and erh1∆. Cluster 2 contains genes that are derepressed in mmi1∆ and mmi1W112A or erh1∆. Cluster 3 contains genes that are derepressed in mmi1∆ only. In total, there are 531 genes considered here as upregulated out of a possible 7019. Source data are provided as a Source Data file. b RNA-seq profiles of 9 representative genes whose repression requires Erh1-Mmi1 interaction. The color scheme used is WT (black), mmi1W112A (red), and erh1∆ (blue). Shown is normalized RPKM expression. c RNA-seq profiles of 3 representative loci showing derepression in mmi1∆ but not in mmi1W112A and erh1∆ cellsFull size imageThe majority of transcripts that showed elevated levels in mmi1W112A and erh1∆ were also upregulated in mmi1∆ (Fig. 6a). However, the levels of upregulated transcripts were generally higher in mmi1∆ cells as compared to mmi1W112A and erh1∆ cells (Fig. 6a and Supplementary Fig. 6b). More importantly, we found that the loss Mmi1 caused upregulation of a large number of coding and non-coding RNAs that were not affected by mmi1W112A or erh1∆ (Fig. 6a, c). We conclude from these analyses that the association between Mmi1 and Erh1 is critical for controlling a specific subset of the Mmi1 regulon, and that Mmi1 regulates gene expression in both EMC-dependent and -independent manners.EMC prevents nuclear export of gametogenic gene transcriptsMmi1 tethers gametogenic gene transcripts to nuclear foci to prevent their translation and expression in mitotically dividing cells42. We wondered whether EMC assembly rather than the individual Mmi1 or Erh1 protein is required for this nuclear sequestration activity. To test this, we assayed the localization of a DSR-containing ssm4 mRNA in mmi1W112A mutant cells that express Mmi1 and Erh1 at levels comparable to wild-type cells but are defective in EMC assembly. Single molecule RNA fluorescence in situ hybridization (smFISH) revealed ssm4 mRNA predominantly localizing to specific nuclear foci in WT, whereas cytoplasmic accumulation of ssm4 mRNAs was observed in mmi1∆ mutant cells (Fig. 7a, b) as observed previously42. Interestingly, ssm4 mRNAs were exported into the cytoplasm of mmi1W112A mutant cells (Fig. 7a, b), suggesting that EMC formation is critical for nuclear retention of DSR-containing transcripts to prevent their untimely expression.Fig. 7EMC assembly is critical for nuclear retention of gametogenic gene transcripts in mitotic cells. a Representative images of the EMC target ssm4 mRNA (red) detected by Single molecule RNA Fluorescence In-Situ Hybridization (smFISH). DNA was stained with DAPI (blue). Images are shown as the maximum-intensity projections of Z-stacks. Dotted lines indicate the outline of cells. Scale bar (white) represents 5 μm. b Quantification of nuclear and cytoplasmic localization of ssm4 mRNA. The upper panel shows the mean ± SEM from more than 140 cells and the lower panel indicates the distribution of the percentages of ssm4 mRNA spots/cellFull size imageMmi1W112A uncouples EMC-dependent and -independent functionsMmi1 also promotes alternative polyadenylation and transcription termination of meiotic mRNAs and regulatory lncRNAs34,35,36. For example, binding of Mmi1 to the ssm4 transcript triggers pre-mature pre-mRNA 3′-end formation near regions containing DSR elements34. This process, which involves the RNA polymerase II termination factor Dhp1/Xrn2 and the nuclear exosome Rrp6, precludes utilization of the canonical polyadenylation (polyA) signal further downstream34. Similarly, elegant studies have shown that Mmi1 selectively promotes termination of lncRNAs involved in developmental and environmental control of gene expression. Specifically, Mmi1 mediates transcription termination to prevent lncRNAs from invading and repressing downstream genes35,36.In light of these previous studies, we wondered whether Mmi1 controls polyA site selection as part of EMC. We utilized the mmi1W112A mutant, in which the Mmi1 mutant protein and Erh1 are expressed at levels comparable to those in WT but fail to form the EMC. 3′-RACE at the ssm4 locus showed that pre-mature 3′-end processing was abolished in mmi1∆, resulting in full-length mRNA terminating at the canonical polyA site (Fig. 8a and Source Data). In contrast, utilization of the canonical polyA signal was not observed in mmi1W112A, which instead displayed usage of cryptic sites in regions containing multiple hexameric DSR elements (Fig. 8a). An identical pattern was observed in erh1∆ (Fig. 8a). These results suggest that EMC assembly is not essential for preventing the use of the canonical polyA signal.Fig. 8Mmi1W112A uncouples EMC-dependent and -independent Mmi1 functions. a 3′ RACE of ssm4 and leu1 (control) loci. Red triangles indicate termination sites as determined by sequencing of 3′ RACE products. The black arrow indicates the gene-specific forward primer used, which can be found in Supplementary Table 4. b RNA-seq expression profiles of prt-pho1 loci and nam1-byr2 in WT, mmi1W112A, erh1∆, and mmi1∆. Shown is normalized RPKM expression. c Northern blot analysis at the prt-pho1 locus in indicated strains using a probe targeting pho1 mRNA (top and bottom panels). d Northern blot analysis at the nam1-byr2 locus in indicated strains using a probe targeting nam1 ncRNA. Source data are provided as a Source Data fileFull size imageWe next wondered whether assembly of EMC is also dispensable for the role of Mmi1 in selective termination of lncRNAs. Notably, RNA-seq analyses revealed that lncRNAs targeted by Mmi1 extended into downstream genes in mmi1∆, but not in mmi1W112A or erh1∆ (Fig. 8b). Northern analyses of prt and nam1 lncRNAs, which regulate expression of downstream pho1 and byr2 genes, respectively19,35,36,43, revealed defective termination of lncRNAs in mmi1∆, but not mmi1W112A or erh1∆ (Fig. 8c, d). Read-through transcripts resulting from defects in termination of prt and nam1 were specifically detected in the mmi1∆ mutant (Fig. 8c, d). These longer transcripts (named prt-L and nam1-L) were not detected in mmi1W112A or erh1∆ (Fig. 8c, d). Defective termination in mmi1∆ but not mmi1W112A or erh1∆ was also observed at other loci (Supplementary Fig. 7). These results suggest that Mmi1 promotes termination of regulatory lncRNAs via a mechanism independent of its interaction with Erh1 or EMC formation.Our analyses using mmiW112A also uncovered an EMC-dependent function of Mmi1 in the repression of pho1 mRNA, a function obscured in mmi1∆ cells, which are defective in both EMC assembly and in the termination of prt lncRNA involved in pho1 repression. Unlike mmi1∆ cells that show only a small change in pho1 gene expression, mmiW112A cells showed a marked increase in the level of pho1 mRNA (Fig. 8b, c). A similar increase was also observed in erh1∆ cells (Fig. 8b, c). These results suggest that Mmi1 represses pho1 expression as part of EMC. However, this function of Mmi1 is obscured in mmi1∆ cells (Fig. 8b). This is due to defective termination of prt lncRNA that permits the long prt transcript to invade and repress pho1 (Fig. 8c top panel). Indeed, deletion of prt alleviated the repression of pho1 observed in mmi1∆ cells (Fig. 8c bottom panel). Similar changes are detected at other loci such as the SPCC11E10.01 gene, which is also repressed by read-through lncRNA in mmi1∆ cells (Supplementary Fig. 7). Thus, the Mmi1W112A mutant that affects Mmi1-Erh1 interaction without disrupting the termination function of Mmi1 provides a unique tool to uncouple EMC-dependent and -independent functions of Mmi1.DiscussionThis study describes the structural and functional analysis of the nuclear RNA processing complex EMC. EMC contains the evolutionarily conserved ERH family protein Erh1 and the YTH-domain RNA-binding protein Mmi1, which prevent the deleterious effects of untimely gametogenic gene expression in mitotic cells9,14,18,41 (this study). Erh1 interacts with Mmi1 through an interface that is conserved in the human ERH protein. The structure-based design of a mutant allele that disrupts Mmi1 binding to the Erh1 interface enabled us to determine the biological significance of EMC assembly. Ultimately, we uncovered a specific requirement for EMC among the various functions attributed to Mmi1 including RNA-mediated heterochromatin assembly, nuclear retention of transcripts, and gametogenic gene silencing.Erh1 associates with well-known RNA processing activities such as CCR4-NOT and MTREC that are linked to mRNA decay and assembly of facultative heterochromatin domains at specific genomic loci14,19,22,25,27,44. The targeting of Erh1 and its associated factors requires Mmi114, which contains two notable domains, including a carboxy-terminal YTH domain implicated in binding to DSR-containing RNAs18,29,30,31,32,33 and a conserved amino-terminal domain that is largely unstructured30(this study). Our analyses show that the region containing the YTH domain of Mmi1 is dispensable for its interaction with Erh1. Instead, it is the amino-terminal domain of Mmi1 (residues 95–122) that interacts with Erh1 to form EMC. These observations suggest that Mmi1-mediated degradation of RNA and heterochromatin formation require cooperation between its carboxy- and amino-terminal domains. Whereas Mmi1 binds target RNAs via its YTH domain, it engages Erh1 and RNA processing complexes via its amino-terminal domain (Supplementary Fig. 8).Our biochemical and co-crystal analyses show that EMC is a heterotetrameric complex, wherein Mmi1 is bound to the surface of the Erh1 dimer interface with 2:2 stoichiometry. In particular, we found that Mmi1 adopts a mixed loop-helix conformation when bound to Erh1. Intra and inter-molecular interactions between Mmi1 and Erh1 are driven by hydrophobic contacts and are supported by hydrogen bonds, with residue Mmi1Trp112 playing a crucial role in the formation or stabilization of EMC. Indeed, our in vitro and in vivo analyses showed that mutation of the Mmi1Trp112 affected its interaction with Erh1, hence compromising the assembly of EMC (Figs. 3d, 4b, and Supplementary Table 1). In light of the structural features of EMC, it is possible that incorporation of Mmi1 into EMC facilitates dimerization, a feature critical for nuclear sequestration of meiotic mRNAs42. Consistent with this possibility, we note that a domain (residues 61–180) reported to be important for Mmi1 self-association42 overlaps with the Mmi1 amino-terminal domain (residues 95–122) and our analyses show that EMC formation is critical for nuclear retention of meiotic mRNAs.Another major finding from our analyses is the highly conserved molecular interface on the Erh1 dimer to which Mmi1 binds. Erh1 homodimers bound to Mmi1 show strong similarities with human ERH homodimers (this study)37,45. The high conservation of the binding pocket and dimerization interface is surprising because, at the primary sequence level, the evolutionarily distant Erh1 and ERH share <30% amino acid identity. This structural conservation suggests that ERH in other species may use the same interface to interact with its binding partners to regulate expression of specific target genes.Importantly, structure-guided design of a mutant allele enabled us to dissect the role of EMC in various functions ascribed to Mmi1. Although several activities have been reported for Mmi118,23,26,27,28,34,35,36,42, which of them require association of Mmi1 with Erh1 to form EMC, and which require only the individual protein, remained to be elucidated. Because the mmi1W112A mutant disrupted Mmi1-Erh1 without affecting protein levels, we were able to discover that the Mmi1-Erh1 interaction is indeed required for RNA-mediated assembly of heterochromatin islands targeting meiotic genes. Moreover, EMC assembly is required for silencing a specific subset of the entire Mmi1 regulon. Surprisingly, EMC is dispensable for Mmi1-dependent premature pre-mRNA 3′-end formation of meiotic transcripts and termination of regulatory lncRNAs. Indeed, only the strain carrying a deletion of mmi1, and not the mutant defective in EMC assembly (mmi1W112A), showed defects in termination of target transcripts. This finding suggests that Mmi1 also acts independently to engage additional factors involved in termination and gene regulation.The ability to specifically disrupt EMC in the mmi1W112A mutant, without interfering with the termination function of Mmi1, provided insights into gene regulation that could not be revealed using the mmi1∆ null allele. For example, Mmi1 participates in overlapping mechanisms to control expression of genes located adjacent to cis-acting regulatory lncRNA (such as pho1). As part of EMC, which is associated with RNA processing activities, Mmi1 represses pho1 mRNA. Mmi1 also acts independently of EMC to modulate pho1 expression by mediating transcription termination of the upstream lncRNA, thus preventing it from invading and repressing pho1. Indeed, the strong upregulation of pho1 observed in mmi1W112A cells, which are defective only in EMC assembly, is obscured in mmi1∆ cells by the invasion of lncRNA defective in Mmi1-mediated termination (Fig. 8b, c). The interplay between overlapping Mmi1-dependent mechanisms at environmentally or developmentally regulated loci remains to be determined, but it is plausible that such a system facilitates rapid fine-tuning of gene expression during abrupt changes. Whether Mmi1 affects the loading of gene silencing factors such as HDACs implicated in lncRNA-mediated silencing of genes is also unknown46,47.Collectively, we provide important insight into EMC and open up other avenues for investigating conserved ERH and YTH family proteins16,48,49. Structural similarities and the highly conserved Erh1 interaction interface from S. pombe to human suggest that ERH family members may all contain a structurally conserved scaffold for connecting with species-specific proteins to mediate diverse cellular functions. Since protein–protein interactions are primarily driven by structural attributes, the ERH interface may be evolutionarily conserved due to its ability to recognize intrinsically disordered regions (IDRs) crucial for the functions of various RNA-binding proteins50. As RNA-binding proteins have evolved to recognize species-specific RNA substrates, ERH family members might provide a conserved link between these RNA-binding proteins and RNA-processing effectors. Further probing of the molecular architecture and functions of the ERH and YTH proteins that control several different aspects of RNA metabolism is crucial for understanding how these proteins prevent aberrant gene expression and chromosomal abnormalities11,41, and may reveal therapeutic targets for treatment of human diseases.MethodsProtein expression and purificationA region of Erh1 (residues 1–104) was amplified by PCR from the S. pombe genome and cloned into a modified pET28a (Novagen) vector without a thrombin protease cleavage site (p28a). GST-Mmi1YTH was sub-cloned from a Mmi1YTH-p28a construct to a modified PGex-4T1 vector with a TEV protease cleavage site (Tev4T1). A region of Mmi1 (residues 1-122) was amplified by PCR from the S. pombe genome and cloned into the Tev4T1 vector. GST-tagged Mmi165–122, Mmi95–122, Mmi1195–111, and Mmi1102–111 were generated from the Mmi11–122]-Tev4T1 construct by a MutanBEST kit (Takara). SUMO tagged Mmi195–122 was sub-cloned from the Mmi95–122-Tev4T1 construct to a modified pET28a vector with a SUMO protein fused at the N-terminus following the His6 tag. Mutants were generated using the Takara MutanBEST Kit. The Erh1-(Gly-Ser-Ser)5-Mmi195–122 fusion clone was constructed by overlap extension PCR and was also cloned to the p28a vector. All proteins were expressed in Escherichia coli BL21 (Gold) cells. Cells were grown in LB medium at 37 °C until the OD600 reached about 0.8. Protein expression was induced with 0.1 mM β-d-1-thiogalactopyranoside (IPTG) for 24 h at 16 °C. The His6-tagged proteins, as well as SUMO tagged Mmi1 peptides, were purified by Ni-chelating resin (Qiagen) in a buffer containing 20 mM Tris-HCl (pH 8.0), 500 mM NaCl. The GST tagged proteins were purified by glutathione sepharose (GE healthcare) in a buffer containing 20 mM Tris-HCl (pH 7.5), 500 mM NaCl. Proteins were further purified by size-exclusion chromatography on a Hiload 16/60 Superdex 75 column (GE healthcare) in a buffer containing 20 mM Tris-HCl (pH 7.5), 150 mM NaCl.CrystallographyThe crystals were grown using the hanging drop vapor diffusion method at 20 °C by mixing 1 µl Erh1-(Gly-Ser-Ser)5-Mmi195–122 fusion protein (10 mg per mL) with 1 µl reservoir buffer (1.6 M (NH4)2SO4, 0.1 M MES pH 6.5). The reservoir solution supplemented with 25% glycerol was used as a cryoprotectant. The X-ray diffraction data set was collected on beamline 18U1 at Shanghai Synchrotron Radiation Facility (SSRF BL18U1). The data set was indexed and integrated by iMosflm and scaled by SCALA in CCP4i suite51,52. The initial crystallographic phases were calculated using molecular replacement that was carried out by Phaser employing the structure of human ERH protein (PDB ID: 1WZ7) as the search model53. An initial model was automatically built by Buccaneer54. The model was further built and refined using Coot and Phenix, respectively55,56.Isothermal titration calorimetryITC assays were carried out on a MicroCal iTC200 calorimeter (GE Healthcare) at 293 K. Because a synthesized Mmi195–122 peptide could not be dissolved in the interaction buffer (20 mM Tris-HCl pH 7.5, 150 mM NaCl), and the protein construct corresponding to Mmi195–122 precipitated upon removal of the solubility tag, likely due to a high proportion of hydrophobic residues in the sequence, we conducted the ITC experiments using SUMO-tagged Mmi1 peptides for titration into Erh1. The titration protocol consisted of a single initial injection of 1 µl, followed by 19 injections of 2 µl SUMO-tagged Mmi1 peptides into the sample cell containing Erh1 protein. Thermodynamic data were analyzed with a single-site binding model using MicroCal PEAQ-ITC Analysis Software provided by the manufacturer.Strains and mediaStandard yeast culturing and genetic manipulation methods were used. S. pombe strains used in this study are listed in Supplementary Table 4. Strains carrying the prt∆ allele contain a deletion of the region −400 to −1200 bp upstream of pho119. All in vivo experiments were performed in yeast extract rich medium supplemented with adenine (YEA) at 18 °C, 32 °C, or 37 °C, as indicated.Construction of Mmi1W112A

S. pombe strainsThe untagged mmi1W112A strain was constructed using the approach outlined in Supplementary Fig. 4a. The 5′ region of mmi1 and an upstream homology region were amplified so that the W112A mutation was designed as part of the reverse primer with 80 bp downstream homology region. The resultant amplicon was transformed into a strain containing ura4+ inserted adjacent to mmi1. Transformants in which the ura4+ was popped-out by the PCR amplicon were identified using counterselective FOA medium. Sanger sequencing was used to verify the presence of the W112A mutation.The flag-mmi1W112A strain was constructed by first amplifying the mmi1W112A coding region from the untagged strain described above. The resultant amplicon was co-transformed with pREP3X plasmid, carrying a LEU2 selection marker, into a flag-mmi1 (wild-type mmi1) strain. Transformants were selected on medium lacking leucine at 32 °C to obtain single colonies. Single colonies were replica plated onto rich YEA medium plates and further incubated at 18 °C or 32 °C. Transformants carrying flag-mmi1W112A were identified based on their poor growth at 18 °C. Sanger sequencing of the mmi1 gene amplified from the mutant strain was used to verify the presence of the mutant allele. Western blotting was performed to confirm protein expression levels, as shown in Fig. 4a.Immunoprecipitation and Western blottingCells were grown to mid-log phase in rich YEA medium at 32 °C, harvested, and flash-frozen in liquid nitrogen prior to extract preparations. Extracts prepared from yeast cells expressing epitope tagged proteins under the control of native gene promoters were used for immunoprecipitations and Western blot analyses as described28. Total protein extracts for western blotting analyses were prepared by trichloroacetic acid (TCA) precipitation. Briefly, cells were lysed using glass beads in 20% TCA buffer. Next, lysates were diluted using 5% TCA buffer and total protein pellets were concentrated by centrifugation at 21,000×g for 5 min. Precipitated protein was dissolved in sodium dodecyl sulfate (SDS) sample buffer prior to resolution in a polyacrylamide gel. For immunoprecipitation experiments, cells were lysed using glass beads in 2X HC lysis buffer (300 mM HEPES buffer pH 7.6, 100 mM KCl, 2 mM EDTA, 0.2% NP-40, and 0.2 mM DTT) containing protease inhibitor cocktail (11697498001, Roche) and 2 mM PMSF. Lysate cleared of cellular debris was incubated with antibody-conjugated beads for immunoprecipitation. Afterwards, beads were washed three times with 1X HC lysis buffer (150 mM HEPES pH 7.6, 250 mM KCl, 1 mM EDTA, 1 mM PMSF, 0.1% NP-40, and 1 tablet protease inhibitor cocktail per 100 mL volume) and twice with AC200 wash buffer (20 mM HEPES pH 7.6, 1 mM EGTA, 200 mM KCl, 2 mM MgCl2 0.1% NP-40, 1 mM PMSF, and 1 tablet protease inhibitor cocktail per 100 mL volume). Protein elution was performed using 0.2 M glycine (pH 2). Eluted protein was precipitated by TCA precipitation and dissolved into SDS sample buffer prior to resolution in a polyacrylamide gel. Antibodies used at 1:1000 dilution were: Anti-FLAG (M2, Sigma), anti-GFP (7.1 and 13.1, Roche and gta20, Chromotek), and anti-Cdc2 (Y100.4, Santa Cruz). Ponceau S (Sigma) staining was used to visualize the total protein loaded.ChIP-qPCR and ChIP-seqChIP experiments were performed as described40. 25 OD595 of cells were harvested from YEA cultures grown to mid-log phase at 32 °C. Cells were fixed with 1% formaldehyde for 20 min at room temperature. For Erh1-ChIP, additional fixation with dimethyl adipimidate (Thermo Fisher Scientific) for 45 min at room temperature was performed. Cell pellets were suspended into 400 µL of ChIP lysis buffer (50 mM HEPES pH 7.5, 140 mM NaCl, 1 mM EDTA, 1% Triton, and 0.1% deoxycholate) and glass beads. Cell lysis was performed using a bead-beater and genomic DNA was sonicated using a Bioruptor (Diagenode) 12-cycles on medium power setting (30 s on, 30 s off) at 4 °C. Cellular debris was removed by centrifugation at 1500×g for 5 minutes at 4 °C. Lysate supernatant and brought up to 1 mL volume using ChIP lysis buffer and was precleared using 20 µL of Protein A/G-plus agarose slurry (Santa Cruz) with rotation for 1 h at 4 °C. Precleared lysates were centrifuged at 1000×g for 1 mine and lysate supernatant was transferred to a new tube for subsequent immunoprecipitation. Fifty microlitre of lysate was reserved as whole-cell extract input control. Anti-H3K9me2 (2μg per ChIP, ab115159, Abcam) and anti-GFP (10μg per ChIP, ab290, Abcam) antibodies were used for immunoprecipitation overnight at 4 °C. Antibodies were recovered using 20 µL of Protein A/G-plus agarose slurry (Santa Cruz) with rotation for 4 h at 4 °C. Beads were washed twice with ChIP lysis buffer, twice with ChIP high-salt buffer (50 mM HEPES pH 7.5, 500 NaCl, 1 mM EDTA, 1% Triton, 0.1% deoxycholate), twice with ChIP wash buffer III (10 mM Tris-HCl pH 8, 0.25 M LiCl, 0.5% NP-40, 0.5% deoxycholate, and 1 mM EDTA), and once with 1X TE pH 8. DNA was eluted by heating beads at 65 °C for 1 h in 100 µL of ChIP elution buffer (1X TE pH 8, 1% SDS). After elution, NaCl was added to bring the concentration up to 100 mM. Crosslinking was reversed by heating at 65 °C overnight. RNA and protein were removed by treatment with RNase A (Sigma) and proteinase K (Thermo Fisher Scientific). DNA was purified using PCR purification kit (Qiagen) according to manufacturer instructions. Immunoprecipitated DNA or input DNA was analyzed by qPCR or Illumina sequencing.For ChIP-qPCR analyses, experiments were performed using iTaq Universal SYBR Green Supermix (Biorad). Oligonucleotides used for ChIP-qPCR are listed in Supplementary Table 4. For ChIP-seq analyses, sequencing libraries were generated using NEBNext Ultra II DNA library prep kit for Illumina (NEB) according to the manufacturer’s protocol. Samples were multiplexed and single-end reads were sequenced on the Illumina NextSeq 500 platform. Adapter trimmed reads were aligned to the S. pombe v2.29 reference genome using BWA-MEM. Correction for GC-content bias and input normalization was performed using the Deeptools suite57 functions correctGCbias and bamCompare. Plots were generated using the plotProfile function.RNA-seq and RT-PCRTotal RNA was prepared by harvesting 2 OD595 of mid-log phase cells cultured in YEA medium at 32 °C followed by flash-freezing in liquid nitrogen. RNA was isolated using the hot-phenol method in equal volumes of AES buffer (50 mM sodium acetate pH 5.3, 10 mM DTA, 1% SDS) and acid-phenol. The mixture was incubated at 65 °C and vortexed every minute for 5 minutes. Afterwards, the slurry was transferred to Maxtract High Density tubes (Qiagen) and RNA was purified by chloroform extraction. Purified RNA was precipitated using Glycoblue (Thermo Fisher Scientific), sodium acetate pH 5.3 and isopropanol. Total RNA was treated with DNase I (Thermo Fisher Scientific) before subsequent analyses. For RNA-seq, ribosomal RNAs were depleted using the Ribo-Zero Gold rRNA Removal Magnetic Kit (Yeast) (Epicentre) prior to library construction using the NEBNext Ultra II Directional RNA library prep kit for Illumina (NEB) according to the manufacturer’s instructions. Single-end sequencing was performed on the Illumina NextSeq 500 platform. Adapter trimmed reads were aligned to the S. pombe v2.29 reference genome using Tophat258. Minimum and maximum intron sizes were set to 30 and 817, respectively. Normalization by reads per kilobase per million (RPKM) and coverage plots were performed using the Deeptools suite function57 bamCoverage and plotProfile. For differential analyses, FPKM values were determined for each of the 7019 genes using Cufflinks59. Upregulated genes were defined as those with FPKM ratios ≥2 relative to WT. Heatmaps were generated using Java Treeview platform60.For RT-PCR experiments, cDNA was synthesized using Superscript III First-Strand Synthesis SuperMix (Thermo Fisher Scientific) using oligo-dT. Subsequent qPCR analyses were performed using iTaq Universal SYBR Green Supermix (Biorad). Oligonucleotides used for RT-PCR are listed in Supplementary Table 4.smFISHSingle molecule RNA Fluorescence In-Situ Hybridization (smFISH) was performed with modifications to the manufacturer’s protocol (Biosearch Technologies) and as described61. Mid-log cells were fixed in 3.7% formaldehyde and treated with Zymolyase 100 T for partial cell wall digestion. The cells were permeabilized in 70% ethanol and incubated overnight with probes against ssm4 mRNA. CAL Fluor Red 590 labeled ssm4 probes were designed using Stellaris Probe Designer tool (Supplementary Table 4) and synthesized by Biosearch Technologies. Stellaris RNA FISH hybridization and wash buffers were obtained from Biosearch Technologies. Cells were mounted in ProLong Gold antifade reagent with DAPI (Life Technologies) and imaged using a DeltaVision Elite fluorescence microscope (Applied Precision, GE Healthcare) with Olympus 100×/1.40 objective. Optical Z sections were acquired (0.2 µ step size, 20 sections) for each field. Images were deconvolved and all Z-stacks were projected into a single plane as maximum-intensity projections. Fiji (ImageJ) software was used for analysis. Cell boundaries were marked manually and the distribution of ssm4 mRNA spots was calculated manually.Northern blot analysisNorthern blot analysis was performed using total RNA isolated as described above for RNA-seq analyses. Ten microgram of total RNA was loaded per lane in a 1% formaldehyde agarose gel. T7 MAXIscript kit (Ambion) was used to generate α-P32-UTP (PerkinElmer) labeled RNA probes and hybridizations were carried out using the NorthernMax kit (Ambion) according to manufacturer instructions. Uncropped gel images are provided as a Source Data file.Spotting assayMid-log phase yeast cells were serially diluted fourfold and spotted onto YEA agar medium plates. Spotted plates were incubated at 18, 32, or 37 °C for 2–6 days. erh1∆ served as a known hypersensitive control at 18 °C14, while mmi1-ts6 served as a known hypersensitive control at 37 °C.Reporting summaryFurther information on experimental design is available in the Nature Research Reporting Summary linked to this article.

Data availability

The atomic coordinates and structure factors for the EMC complex have been deposited to the Protein Data Bank (PDB) under the accession code PDB 6AKJ. Genomic datasets are deposited in the Gene Expression Omnibus with accession numbers GSE119604 and GSE119605. All other materials are available from the corresponding authors upon reasonable request. Uncropped gel images and other source data underlying Figs. 1b–d, 3d, 4a, b and e, 6a, 8a, c, d are provided as a Source Data file. A Reporting Summary for this article is available as a Supplementary Information file.

ReferencesFeng, S., Jacobsen, S. E. & Reik, W. Epigenetic reprogramming in plant and animal development. Science 330, 622–627 (2010).Article 

ADS 

CAS 

Google Scholar 

Lopez-Maury, L., Marguerat, S. & Bahler, J. Tuning gene expression to changing environments: from rapid responses to evolutionary adaptation. Nat. Rev. Genet. 9, 583–593 (2008).Article 

CAS 

Google Scholar 

Cantone, I. & Fisher, A. G. Epigenetic programming and reprogramming during development. Nat. Struct. Mol. Biol. 20, 282–289 (2013).Article 

CAS 

Google Scholar 

Grewal, S. I. & Jia, S. Heterochromatin revisited. Nat. Rev. Genet. 8, 35–46 (2007).Article 

CAS 

Google Scholar 

Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).Article 

CAS 

Google Scholar 

Kilchert, C., Wittmann, S. & Vasiljeva, L. The regulation and functions of the nuclear RNA exosome complex. Nat. Rev. Mol. Cell Biol. 17, 227–239 (2016).Article 

CAS 

Google Scholar 

Lykke-Andersen, S. & Jensen, T. H. Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes. Nat. Rev. Mol. Cell Biol. 16, 665–677 (2015).Article 

CAS 

Google Scholar 

Rinn, J. L. & Chang, H. Y. Genome regulation by long noncoding RNAs. Annu. Rev. Biochem. 81, 145–166 (2012).Article 

CAS 

Google Scholar 

Yamamoto, M. The selective elimination of messenger RNA underlies the mitosis-meiosis switch in fission yeast. Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 86, 788–797 (2010).Article 

CAS 

Google Scholar 

Portela, A. & Esteller, M. Epigenetic modifications and human disease. Nat. Biotechnol. 28, 1057–1068 (2010).Article 

CAS 

Google Scholar 

Simpson, A. J., Caballero, O. L., Jungbluth, A., Chen, Y. T. & Old, L. J. Cancer/testis antigens, gametogenesis and cancer. Nat. Rev. Cancer 5, 615–625 (2005).Article 

CAS 

Google Scholar 

Mata, J., Lyne, R., Burns, G. & Bahler, J. The transcriptional program of meiosis and sporulation in fission yeast. Nat. Genet. 32, 143–147 (2002).Article 

CAS 

Google Scholar 

Krzyzanowski, M. K., Kozlowska, E. & Kozlowski, P. Identification and functional analysis of the erh1( + ) gene encoding enhancer of rudimentary homolog from the fission yeast Schizosaccharomyces pombe. PLoS One 7, e49059 (2012).Article 

ADS 

CAS 

Google Scholar 

Sugiyama, T. et al. Enhancer of rudimentary cooperates with conserved RNA-processing factors to promote meiotic mRNA decay and facultative heterochromatin assembly. Mol. Cell 61, 747–759 (2016).Article 

CAS 

Google Scholar 

Yamashita, A., Takayama, T., Iwata, R. & Yamamoto, M. A novel factor Iss10 regulates Mmi1-mediated selective elimination of meiotic transcripts. Nucleic Acids Res. 41, 9680–9687 (2013).Article 

CAS 

Google Scholar 

Weng, M. T. & Luo, J. The enigmatic ERH protein: its role in cell cycle, RNA splicing and cancer. Protein Cell 4, 807–812 (2013).Article 

CAS 

Google Scholar 

Meola, N. et al. Identification of a nuclear exosome decay pathway for processed transcripts. Mol. Cell 64, 520–533 (2016).Article 

CAS 

Google Scholar 

Harigaya, Y. et al. Selective elimination of messenger RNA prevents an incidence of untimely meiosis. Nature 442, 45–50 (2006).Article 

ADS 

CAS 

Google Scholar 

Lee, N. N. et al. Mtr4-like protein coordinates nuclear RNA processing for heterochromatin assembly and for telomere maintenance. Cell 155, 1061–1074 (2013).Article 

CAS 

Google Scholar 

St-Andre, O. et al. Negative regulation of meiotic gene expression by the nuclear poly(A)-binding protein in fission yeast. J. Biol. Chem. 285, 27859–27868 (2010).Article 

CAS 

Google Scholar 

Sugiyama, T. & Sugioka-Sugiyama, R. Red1 promotes the elimination of meiosis-specific mRNAs in vegetatively growing fission yeast. EMBO J. 30, 1027–1039 (2011).Article 

CAS 

Google Scholar 

Stowell, J. A. W. et al. Reconstitution of targeted deadenylation by the Ccr4-Not complex and the YTH domain protein Mmi1. Cell Rep. 17, 1978–1989 (2016).Article 

CAS 

Google Scholar 

Yamanaka, S. et al. RNAi triggered by specialized machinery silences developmental genes and retrotransposons. Nature 493, 557–560 (2013).Article 

ADS 

CAS 

Google Scholar 

Zhou, Y. et al. The fission yeast MTREC complex targets CUTs and unspliced pre-mRNAs to the nuclear exosome. Nat. Commun. 6, 7050 (2015).Article 

Google Scholar 

Cotobal, C. et al. Role of Ccr4-Not complex in heterochromatin formation at meiotic genes and subtelomeres in fission yeast. Epigenetics Chromatin 8, 28 (2015).Article 

Google Scholar 

Hiriart, E. et al. Mmi1 RNA surveillance machinery directs RNAi complex RITS to specific meiotic genes in fission yeast. EMBO J. 31, 2296–2308 (2012).Article 

CAS 

Google Scholar 

Tashiro, S., Asano, T., Kanoh, J. & Ishikawa, F. Transcription-induced chromatin association of RNA surveillance factors mediates facultative heterochromatin formation in fission yeast. Genes Cells 18, 327–339 (2013).Article 

CAS 

Google Scholar 

Zofall, M. et al. RNA elimination machinery targeting meiotic mRNAs promotes facultative heterochromatin formation. Science 335, 96–100 (2012).Article 

ADS 

CAS 

Google Scholar 

Chatterjee, D., Sanchez, A. M., Goldgur, Y., Shuman, S. & Schwer, B. Transcription of lncRNA prt, clustered prt RNA sites for Mmi1 binding, and RNA polymerase II CTD phospho-sites govern the repression of pho1 gene expression under phosphate-replete conditions in fission yeast. RNA 22, 1011–1025 (2016).Article 

CAS 

Google Scholar 

Stowell, J. A. W. et al. A low-complexity region in the YTH domain protein Mmi1 enhances RNA binding. J. Biol. Chem. 293, 9210–9222 (2018).Article 

CAS 

Google Scholar 

Wang, C. et al. A novel RNA-binding mode of the YTH domain reveals the mechanism for recognition of determinant of selective removal by Mmi1. Nucleic Acids Res. 44, 969–982 (2016).Article 

CAS 

Google Scholar 

Wu, B. et al. Structural insights into the specific recognition of DSR by the YTH domain containing protein Mmi1. Biochem. Biophys. Res. Commun. 491, 310–316 (2017).Article 

CAS 

Google Scholar 

Yamashita, A. et al. Hexanucleotide motifs mediate recruitment of the RNA elimination machinery to silent meiotic genes. Open Biol. 2, 120014 (2012).Article 

Google Scholar 

Chalamcharla, V. R., Folco, H. D., Dhakshnamoorthy, J. & Grewal, S. I. Conserved factor Dhp1/Rat1/Xrn2 triggers premature transcription termination and nucleates heterochromatin to promote gene silencing. Proc. Natl Acad. Sci. USA 112, 15548–15555 (2015).ADS 

CAS 

PubMed 

Google Scholar 

Shah, S., Wittmann, S., Kilchert, C. & Vasiljeva, L. lncRNA recruits RNAi and the exosome to dynamically regulate pho1 expression in response to phosphate levels in fission yeast. Genes Dev. 28, 231–244 (2014).Article 

CAS 

Google Scholar 

Touat-Todeschini, L. et al. Selective termination of lncRNA transcription promotes heterochromatin silencing and cell differentiation. EMBO J. 36, 2626–2641 (2017).Article 

CAS 

Google Scholar 

Wan, C., Tempel, W., Liu, Z. J., Wang, B. C. & Rose, R. B. Structure of the conserved transcriptional repressor enhancer of rudimentary homolog. Biochemistry 44, 5017–5023 (2005).Article 

CAS 

Google Scholar 

Bresch, C., Muller, G. & Egel, R. Genes involved in meiosis and sporulation of a yeast. Mol. Gen. Genet. 102, 301–306 (1968).Article 

CAS 

Google Scholar 

Reyes-Turcu, F. E. & Grewal, S. I. Different means, same end-heterochromatin formation by RNAi and RNAi-independent RNA processing factors in fission yeast. Curr. Opin. Genet. Dev. 22, 156–163 (2012).Article 

CAS 

Google Scholar 

Cam, H. P. et al. Comprehensive analysis of heterochromatin- and RNAi-mediated epigenetic control of the fission yeast genome. Nat. Genet. 37, 809–819 (2005).Article 

CAS 

Google Scholar 

Folco, H. D. et al. Untimely expression of gametogenic genes in vegetative cells causes uniparental disomy. Nature 543, 126–130 (2017).Article 

ADS 

CAS 

Google Scholar 

Shichino, Y., Otsubo, Y., Kimori, Y., Yamamoto, M. & Yamashita, A. YTH-RNA-binding protein prevents deleterious expression of meiotic proteins by tethering their mRNAs to nuclear foci. Elife 7, e32155 (2018).Ard, R. & Allshire, R. C. Transcription-coupled changes to chromatin underpin gene silencing by transcriptional interference. Nucleic Acids Res. 44, 10619–10630 (2016).Article 

CAS 

Google Scholar 

Bronner, C., Salvi, L., Zocco, M., Ugolini, I. & Halic, M. Accumulation of RNA on chromatin disrupts heterochromatic silencing. Genome Res. 27, 1174–1183 (2017).Article 

Google Scholar 

Arai, R. et al. Crystal structure of an enhancer of rudimentary homolog (ERH) at 2.1 Angstroms resolution. Protein Sci. 14, 1888–1893 (2005).Article 

CAS 

Google Scholar 

Camblong, J., Iglesias, N., Fickentscher, C., Dieppois, G. & Stutz, F. Antisense RNA stabilization induces transcriptional gene silencing via histone deacetylation in S. cerevisiae. Cell 131, 706–717 (2007).Article 

CAS 

Google Scholar 

Watts, B. R. et al. Histone deacetylation promotes transcriptional silencing at facultative heterochromatin. Nucleic Acids Res. 46, 5426–5440 (2018).Article 

CAS 

Google Scholar 

Patil, D. P., Pickering, B. F. & Jaffrey, S. R. Reading m(6)A in the transcriptome: m(6)A-binding proteins. Trends Cell Biol. 28, 113–127 (2018).Article 

CAS 

Google Scholar 

Stoilov, P., Rafalska, I. & Stamm, S. YTH: a new domain in nuclear proteins. Trends Biochem. Sci. 27, 495–497 (2002).Article 

CAS 

Google Scholar 

Protter, D. S. W. et al. Intrinsically disordered regions can contribute promiscuous interactions to RNP granule assembly. Cell Rep. 22, 1401–1412 (2018).Article 

CAS 

Google Scholar 

Battye, T. G., Kontogiannis, L., Johnson, O., Powell, H. R. & Leslie, A. G. iMOSFLM: a new graphical interface for diffraction-image processing with MOSFLM. Acta Crystallogr. D Biol. Crystallogr. 67, 271–281 (2011).Article 

CAS 

Google Scholar 

Winn, M. D. et al. Overview of the CCP4 suite and current developments. Acta Crystallogr. D Biol. Crystallogr. 67, 235–242 (2011).Article 

CAS 

Google Scholar 

McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007).Article 

CAS 

Google Scholar 

Cowtan, K. The Buccaneer software for automated model building. 1. Tracing protein chains. Acta Crystallogr. D Biol. Crystallogr. 62, 1002–1011 (2006).Article 

Google Scholar 

Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010).Article 

CAS 

Google Scholar 

Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010).Article 

CAS 

Google Scholar 

Ramirez, F. et al. deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 44, W160–W165 (2016).Article 

CAS 

Google Scholar 

Kim, D. et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 14, R36 (2013).Article 

Google Scholar 

Trapnell, C. et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat. Biotechnol. 28, 511–515 (2010).Article 

CAS 

Google Scholar 

Saldanha, A. J. Java Treeview--extensible visualization of microarray data. Bioinformatics 20, 3246–3248 (2004).Article 

CAS 

Google Scholar 

Keifenheim, D. et al. Size-dependent expression of the mitotic activator Cdc25 suggests a mechanism of size control in fission yeast. Curr. Biol. 27, 1491–1497 e1494 (2017).Article 

CAS 

Google Scholar 

Buchan, D. W., Minneci, F., Nugent, T. C., Bryson, K. & Jones, D. T. Scalable web services for the PSIPRED Protein Analysis Workbench. Nucleic Acids Res. 41, W349–W357 (2013).Article 

Google Scholar 

Capra, J. A. & Singh, M. Predicting functionally important residues from sequence conservation. Bioinformatics 23, 1875–1882 (2007).Article 

CAS 

Google Scholar 

Download referencesAcknowledgementsWe thank Masayuki Yamamoto (National Institute of Basic Biology, Japan) for providing mmi1-ts6 mutant strain, Diego Folco and Martin Zofall for their help with imaging and genomics methods, Xiaoling Bao, Rongsheng Ma, Xiaodan Liu, and Tiantian Liu for help with biochemical assays, David Wheeler for help with bioinformatic analyses, Jemima Barrowman for editing the manuscript, and members of our labs for discussions. We also thank the staff of BL18U1 beamline at National Center for Protein Science Shanghai and Shanghai Synchrotron Radiation Facility for assistance during data collection. This work was supported by grants from the Ministry of science and technology of China (2016YFA0500700), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB08010101 and XDPB10), the Chinese National Natural Science Foundation (grant 31330018, 31500590, 31600600, and 31870760), the Fundamental Research Funds for the Central Universities (WK2070000095), the Postdoctoral Research Associate fellowship from the National Institute of General Medical Sciences (1Fi2GM123947-01), and by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. This study used the Helix Systems and Biowulf Linux cluster at the National Institutes of Health.Author informationAuthor notesThese authors contributed equally: Guodong Xie, Tommy V. Vo.Authors and AffiliationsHefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, 230026, Hefei, ChinaGuodong Xie, Beibei Zhang, Yiyang Jiang, Mengqi Lv, Zheng Xu, Chongyuan Wang, Yunyu Shi & Fudong LiLaboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USATommy V. Vo, Gobi Thillainadesan, Sahana Holla, Vanivilasini Balachandran & Shiv I. S. GrewalAuthorsGuodong XieView author publicationsYou can also search for this author in

PubMed Google ScholarTommy V. VoView author publicationsYou can also search for this author in

PubMed Google ScholarGobi ThillainadesanView author publicationsYou can also search for this author in

PubMed Google ScholarSahana HollaView author publicationsYou can also search for this author in

PubMed Google ScholarBeibei ZhangView author publicationsYou can also search for this author in

PubMed Google ScholarYiyang JiangView author publicationsYou can also search for this author in

PubMed Google ScholarMengqi LvView author publicationsYou can also search for this author in

PubMed Google ScholarZheng XuView author publicationsYou can also search for this author in

PubMed Google ScholarChongyuan WangView author publicationsYou can also search for this author in

PubMed Google ScholarVanivilasini BalachandranView author publicationsYou can also search for this author in

PubMed Google ScholarYunyu ShiView author publicationsYou can also search for this author in

PubMed Google ScholarFudong LiView author publicationsYou can also search for this author in

PubMed Google ScholarShiv I. S. GrewalView author publicationsYou can also search for this author in

PubMed Google ScholarContributionsF.L., T.V.V., Y.S., and S.I.S.G. designed the study. G.X. crystallized the EMC. G.X., Y.J., and M.L. collected X-ray data. F.L. determined the crystal structure. G.X., B.Z., Z.X., and C.W. performed in vitro assays. T.V.V. performed majority of in vivo experiments including yeast strain constructions as well as genetic and genomic analyses. V.B. performed biochemical experiments; S.H. performed smFISH experiments; G.T. performed Northern blot experiments. S.I.S.G wrote the paper with input from T.V.V., F.L. and other authors.Corresponding authorsCorrespondence to

Fudong Li or Shiv I. S. Grewal.Ethics declarations

Competing interests

The authors declare no competing interests.

Additional informationJournal peer review information: Nature Communications thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationSupplementary InformationPeer Review FileReporting SummarySource DataRights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissionsAbout this articleCite this articleXie, G., Vo, T.V., Thillainadesan, G. et al. A conserved dimer interface connects ERH and YTH family proteins to promote gene silencing.

Nat Commun 10, 251 (2019). https://doi.org/10.1038/s41467-018-08273-9Download citationReceived: 25 September 2018Accepted: 21 December 2018Published: 16 January 2019DOI: https://doi.org/10.1038/s41467-018-08273-9Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

The inner nuclear membrane protein Lem2 coordinates RNA degradation at the nuclear periphery

Lucía Martín CaballeroMatías CapellaSigurd Braun

Nature Structural & Molecular Biology (2022)

Structural analysis of Red1 as a conserved scaffold of the RNA-targeting MTREC/PAXT complex

Anne-Emmanuelle FoucherLeila Touat-TodeschiniJan Kadlec

Nature Communications (2022)

Molecular basis for PICS-mediated piRNA biogenesis and cell division

Xiaoyang WangChenming ZengChao Xu

Nature Communications (2021)

A scaffold lncRNA shapes the mitosis to meiosis switch

Vedrana AndricAlicia NeversMathieu Rougemaille

Nature Communications (2021)

Diverse heterochromatin-associated proteins repress distinct classes of genes and repetitive elements

Ryan L. McCarthyKelsey E. KaedingKenneth S. Zaret

Nature Cell Biology (2021)

CommentsBy submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Download PDF

Advertisement

Explore content

Research articles

Reviews & Analysis

News & Comment

Videos

Collections

Subjects

Follow us on Facebook

Follow us on Twitter

Sign up for alerts

RSS feed

About the journal

Aims & Scope

Editors

Journal Information

Open Access Fees and Funding

Calls for Papers

Editorial Values Statement

Journal Metrics

Editors' Highlights

Contact

Editorial policies

Top Articles

Publish with us

For authors

For Reviewers

Language editing services

Submit manuscript

Search

Search articles by subject, keyword or author

Show results from

All journals

This journal

Search

Advanced search

Quick links

Explore articles by subject

Find a job

Guide to authors

Editorial policies

Nature Communications (Nat Commun)

ISSN 2041-1723 (online)

nature.com sitemap

About Nature Portfolio

About us

Press releases

Press office

Contact us

Discover content

Journals A-Z

Articles by subject

Protocol Exchange

Nature Index

Publishing policies

Nature portfolio policies

Open access

Author & Researcher services

Reprints & permissions

Research data

Language editing

Scientific editing

Nature Masterclasses

Research Solutions

Libraries & institutions

Librarian service & tools

Librarian portal

Open research

Recommend to library

Advertising & partnerships

Advertising

Partnerships & Services

Media kits

Branded

content

Professional development

Nature Careers

Nature

Conferences

Regional websites

Nature Africa

Nature China

Nature India

Nature Italy

Nature Japan

Nature Korea

Nature Middle East

Privacy

Policy

Use

of cookies

Your privacy choices/Manage cookies

Legal

notice

Accessibility

statement

Terms & Conditions

Your US state privacy rights

© 2024 Springer Nature Limited

Close banner

Close

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Email address

Sign up

I agree my information will be processed in accordance with the Nature and Springer Nature Limited Privacy Policy.

Close banner

Close

Get the most important science stories of the day, free in your inbox.

Sign up for Nature Briefing

Frontiers | ERH Gene and Its Role in Cancer Cells

Frontiers | ERH Gene and Its Role in Cancer Cells

Skip to main content

Top bar navigation Frontiers in Oncology

About us

About us

Who we are MissionValuesHistoryLeadershipAwardsImpact and progress Frontiers' impactProgress Report 2022All progress reportsPublishing model How we publishOpen accessFee policyPeer reviewResearch TopicsServices SocietiesNational consortiaInstitutional partnershipsCollaboratorsMore from Frontiers Frontiers ForumPress officeCareer opportunitiesContact us All journalsAll articles Submit your research Search Frontiers in Oncology

Sections

Sections

Breast CancerCancer Cell SignalingCancer Epidemiology and PreventionCancer GeneticsCancer Imaging and Image-directed InterventionsCancer Immunity and ImmunotherapyCancer MetabolismCancer Molecular Targets and TherapeuticsCardio-OncologyGastrointestinal Cancers: Colorectal CancerGastrointestinal Cancers: Gastric and Esophageal CancersGastrointestinal Cancers: Hepato Pancreatic Biliary CancersGenitourinary OncologyGynecological OncologyHead and Neck CancerHematologic MalignanciesMolecular and Cellular OncologyNeuro-Oncology and Neurosurgical OncologyPediatric OncologyPharmacology of Anti-Cancer DrugsRadiation OncologySkin CancerSurgical OncologyThoracic Oncology ArticlesResearch TopicsEditorial Board

About journal

About journal

Scope Field chief editorsMission & scopeFactsJournal sectionsOpen access statementCopyright statementQualityFor authors Why submit?Article typesAuthor guidelinesEditor guidelinesPublishing feesSubmission checklistContact editorial office

About us

About us

Who we are MissionValuesHistoryLeadershipAwardsImpact and progress Frontiers' impactProgress Report 2022All progress reportsPublishing model How we publishOpen accessFee policyPeer reviewResearch TopicsServices SocietiesNational consortiaInstitutional partnershipsCollaboratorsMore from Frontiers Frontiers ForumPress officeCareer opportunitiesContact us All journalsAll articles Submit your research Frontiers in Oncology

Sections

Sections

Breast CancerCancer Cell SignalingCancer Epidemiology and PreventionCancer GeneticsCancer Imaging and Image-directed InterventionsCancer Immunity and ImmunotherapyCancer MetabolismCancer Molecular Targets and TherapeuticsCardio-OncologyGastrointestinal Cancers: Colorectal CancerGastrointestinal Cancers: Gastric and Esophageal CancersGastrointestinal Cancers: Hepato Pancreatic Biliary CancersGenitourinary OncologyGynecological OncologyHead and Neck CancerHematologic MalignanciesMolecular and Cellular OncologyNeuro-Oncology and Neurosurgical OncologyPediatric OncologyPharmacology of Anti-Cancer DrugsRadiation OncologySkin CancerSurgical OncologyThoracic Oncology ArticlesResearch TopicsEditorial Board

About journal

About journal

Scope Field chief editorsMission & scopeFactsJournal sectionsOpen access statementCopyright statementQualityFor authors Why submit?Article typesAuthor guidelinesEditor guidelinesPublishing feesSubmission checklistContact editorial office Frontiers in Oncology

Sections

Sections

Breast CancerCancer Cell SignalingCancer Epidemiology and PreventionCancer GeneticsCancer Imaging and Image-directed InterventionsCancer Immunity and ImmunotherapyCancer MetabolismCancer Molecular Targets and TherapeuticsCardio-OncologyGastrointestinal Cancers: Colorectal CancerGastrointestinal Cancers: Gastric and Esophageal CancersGastrointestinal Cancers: Hepato Pancreatic Biliary CancersGenitourinary OncologyGynecological OncologyHead and Neck CancerHematologic MalignanciesMolecular and Cellular OncologyNeuro-Oncology and Neurosurgical OncologyPediatric OncologyPharmacology of Anti-Cancer DrugsRadiation OncologySkin CancerSurgical OncologyThoracic Oncology ArticlesResearch TopicsEditorial Board

About journal

About journal

Scope Field chief editorsMission & scopeFactsJournal sectionsOpen access statementCopyright statementQualityFor authors Why submit?Article typesAuthor guidelinesEditor guidelinesPublishing feesSubmission checklistContact editorial office Submit  your research Search Download article

Download PDF

ReadCube

EPUB

XML (NLM)

Share on

Export citation

EndNote

Reference Manager

Simple Text file

BibTex

2,3K

Total views

809

Downloads

6

Citations

Citation numbers are available from Dimensions

View article impact View altmetric score Share on Edited by

FEI CHEN

Stony Brook University, United States

Reviewed by

Chitra Thakur

Stony Brook University, United States

YIRAN QIU

Stony Brook University, United States

Table of contents AbstractThe Expression, Structure and Distribution of the ERHERH Plays a Role in CancerERH Acts as a Protein Partner in CellsFunctions of ERH GeneMolecules that Regulate ERH ExpressionIs ERH a Good Target for Drug Design?ConclusionAuthor ContributionsFundingConflict of InterestPublisher’s NoteAcknowledgmentsReferences Export citation

EndNote

Reference Manager

Simple Text file

BibTex

Check for updates Download article

Download

Download PDF

ReadCube

EPUB

XML (NLM)

REVIEW article Front. Oncol., 23 May 2022

Sec. Molecular and Cellular Oncology

Volume 12 - 2022 |

https://doi.org/10.3389/fonc.2022.900496

This article is part of the Research Topic Reviews in Molecular and Cellular Oncology View all 47 articles ERH Gene and Its Role in Cancer Cells Kun Pang1†Mei-li Li2,3†Lin Hao1Zhen-duo Shi1Harry Feng4Bo Chen1Yu-yang Ma5Hao Xu5Deng Pan5Zhe-Sheng Chen6*Cong-hui Han1*1Department of Urology, Xuzhou Central Hospital, Affiliated Central Hospital of Xuzhou Medical University, Xuzhou, China2Department of Ophthalmology, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou First People's Hospital, Xuzhou, China3Department of Ophthalmology, Eye Disease Prevention and Treatment Institute of Xuzhou, Xuzhou, China4STEM Academic Department, Wyoming Seminary, Kingston, PA, United States5Graduate School, Bengbu Medical College, Bengbu, China6College of Pharmacy and Health Sciences, St. John’s University, New York, NY, United StatesCancer is a major public health problem worldwide. Studies on oncogenes and tumor-targeted therapies have become an important part of cancer treatment development. In this review, we summarize and systematically introduce the gene enhancer of rudimentary homolog (ERH), which encodes a highly conserved small molecule protein. ERH mainly exists as a protein partner in human cells. It is involved in pyrimidine metabolism and protein complexes, acts as a transcriptional repressor, and participates in cell cycle regulation. Moreover, it is involved in DNA damage repair, mRNA splicing, the process of microRNA hairpins as well as erythroid differentiation. There are many related studies on the role of ERH in cancer cells; however, there are none on tumor-targeted therapeutic drugs or related therapies based on the expression of ERH. This study will provide possible directions for oncologists to further their research studies in this field.Cancer is a major public health problem worldwide and is the second leading cause of death in the United States: 1,918,030 new cancer cases and 609,360 cancer deaths are projected to occur in the United States in 2022 (1). However, with the advancement of cancer treatment strategies, cancer mortality has continued to decline since 1991 (2). There have been more and more studies on oncogenes, and tumor-targeted therapies have become an important part of many cancer treatment options (3). Targeted therapies have changed the systemic treatment options for cancer patients. To further prolong the survival time and improve the quality of life of cancer patients, studies on oncogenes for tumor-targeted therapies are ongoing. Recently, more and more studies have shown that the expression of enhancer of rudimentary homolog (ERH) gene is closely related to cancers (4, 5). In this review, we summarize and systematically introduce the ERH gene and its role in cancer cells.In 2007, Jin T et al. first started to suspect and discover the relationship between ERH and malignant tumors (6). They found that the ERH protein was downregulated in von Hippel-Lindau (VHL) tumors with Y98H mutation, but ERH expression was upregulated in many other metastatic tumors. They did not clarify whether the difference in ERH expression was the cause or the result of the VHL tumor. In 2008, Zakrakas M et al. found in their study (7) that comparing with non-tumorigenic breast cancer and normal breast tissue samples, ERH expression is upregulated in tumorigenic cell lines. They also found in ovarian cancer cell lines that, ERH is clearly upregulated with tumor progression. They considered that ERH could be used clinically as a prognostic factor in breast and in ovarian cancers (7). ERH knockdown blocks the cell cycle procession in the G2/M phase (8); this is especially obvious in human Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation-related tumors (such as colorectal, lung and pancreatic cancer) (9).The normal-winged alleles of the rudimentary locus of Drosophila melanogaster encodes a protein possessing the first three enzymatic activities of the pyrimidine biosynthesis pathway (10). Mutations in the rudimentary gene are manifested in a characteristic truncation of the wings, and the severity of the wing truncation is thought to reflect the level of rudimentary gene expression (11). Drosophila enhancer of rudimentary (DROER) is the enhancer of rudimentary locus of Drosophila melanogaster. ERH gene, which was mapped to chromosome 1 band 7q34 by fluorescence in situ hybridization in humans, shares a high sequence identity with DROER (12). Corresponding gene and protein analogues of ERH can be found in various species (13), such as flowering plants (14, 15) (Arabidopsis thaliana), nematodes (Caenorhabditis elegans), and insects (Aedes aegypti). Lower vertebrates (Zebrafish), mammals (Mus musculus), and humans (Homo sapiens) also have a high degree of sequence conservation. ERH is not found in the fungi, except for the fission yeasts Schizosaccharomyces, S. pombe, S. octosporus, S. cryophilus, and S. japonicus (16, 17). It was named ERH in human, DROER in Drosophila, and Xenopus homologue of DROER (XERH) in Xenopus and erh in the other non-human species. In vertebrates, human and mouse erh proteins are exactly the same, and there is only one amino acid (isoleucine-valine) difference from zebrafish; DROER is 76% identical to human and mouse erh proteins, and is 49% similar to nematodes and 40% similar to flowering plants (13).The Expression, Structure and Distribution of the ERHERH protein sequence is highly conserved. ERH protein has 25 hydrophobic amino acid positions, 27 in DROER, 23 in nematodes, and 20 in Arabidopsis. These hydrophobic amino acids are mostly present in 3 conservative α helices (Figure 1A), which is inferred to be an active domain (14). ERH monomeric structure comprises a single domain, and it presents a dimeric structure through 2 beta-sheet regions interacting in the crystal structure (Figures 1A, B) (18, 20). There are two conserved casein kinase II (CKII) phosphorylation sites in the ERH protein (Figure 1C) (13). It is speculated (21) that CKII can change the secondary structure of Enhancer of rudimentary (ER), thereby adjusting the activity of ER, which is confirmed in structural studies (Figure 1D). The overall topology of ERH protein is β1-310-β2-α1-α2-β3-β4-α3 (6).FIGURE 1

Figure 1 (A) Ribbon view of ERH monomer. The α-helices and the β-strands are shown in red and in yellow, respectively. (B) View of the main-chain structures in superimposition of the three ERH monomers in the asymmetric unit. Chains (A–C), are colored red, blue, and green, respectively. The superimposition was carried out with the program lsqkab (Kabsch 1976) in CCP4. (C) The conserved casein kinase II (CKII) phosphorylation sites (Thr18 and Ser24) are shown as a blue stick model. (D) Ribbon view of the interface of the ERH dimer. Cited Figures 1A–D (18, 19). This image was generated using PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC.The mRNA of ERH is expressed maternally, enriched in ectodermal derivatives during development and ubiquitously detectable in adults (22). The XERH is expressed ubiquitously in adult frogs, and the ER transcript is present in the egg and at an increased level during organogenesis; it has been detected in tissues derived from the ectoderm (23). The human ER transcript was found in many normal tissues, including the fetus (12). The XERH protein is distributed in the cytoplasm with only minute amounts in the nucleus (23), but another study (24) showed that the ERH protein can interact with nuclear protein FCP1 and distributed in nucleus, contrary to a previous XERH study. ERH was later shown to localize in both the nucleus and nucleolus in human cells (25).ERH Plays a Role in CancerAccording to our review of relevant previous studies, the ERH gene is more expressed in bladder cancer than in normal bladder tissue, and promotes proliferation as well as inhibits cell death (26). Further study showed that ERH can regulate the expression of myelocytomatosis (MYC)gene to have an effect in the migration and invasion of T24 and 5637 bladder cancer cells (27). The study by Balic J et al. (28) showed that the combination of ERH and Pontin acts on signal transducer and activator of transcription-3 (STAT3) to enhance the transcriptional activation of its target genes in gastric cancer cells. Pontin is a highly conserved member of the ATPase family, which plays a vital role in the phosphorylation of tryptophan 2 and transcription extension of RNA Pol II (28). Activated STAT3 can interact with other transcription factors (such as STAT1, c-Jun/c-Fos), and can also induce the expression of other transcription factors (such as MYC) to indirectly affect cell transcription (29). STAT3 can combine with Nuclear Factor-κB (NF-κB) to drive unique transcription signals, including genes related to carcinogenesis and immunity (30). These results are consistent with our later studies (31). Our studies showed that ERH gene could affect the apoptosis of bladder cancer T24 cells through the toll-like receptor (TLR), NF-κB, tumor necrosis factor (TNF) or transforming growth factor-β (TGF-β) signaling pathways, and could be a regulator of kinase tyrosine receptor ligand (KITLG) and an activator of malignant tumors growth (32). In 2020, Zhang D et al. (33) found that ERH can regulate the epithelial-mesenchymal transition (EMT) to affect cell proliferation, apoptosis, invasion and migration in ovarian cancer cells.ERH Acts as a Protein Partner in CellsDimerization Cofactor of Hepatocyte Nuclear Factor-1/Pterin-4α-Carbinolamine DehydrataseAnalyzed by Yeast Two-Hybrid (YTH) Assay, Pogge et al. (23) demonstrated that ERH is a protein partner of DCoH/PCD, which is related to the DNA-binding domain of galectin 4 (GAL4) transcription factor (34) and regulates cell growth (Figure 2). They found partial co-localization of ERH and DCoH/PCD proteins, and that ERH acts as a transcriptional repressor in a cell type-specific manner upon recruitment to the deoxyribonucleic acid (DNA) via its interaction partner DCoH/PCD or by the DNA-binding domain of the GAL4 transcription factor (23). But they did not delve into the specific sites where the two proteins bind, and the report lacked direct evidence of binding. As ERH is a partner of dimerization co-factor of HNF-1 and which is involved in the cell development and regulation in many kinds of cancers, ERH may become a therapeutic target to inhibit the HNF-1 expression.FIGURE 2

Figure 2 Schematic diagram of the role of ERH proteins as molecular partners in cells. The ERH protein, as a nuclear protein, can interact with many proteins such as DCoH/PCD, SPT5, PDIP46/SKAR, Ciz1, HOTS, SNRPD-3 and DEPDC1B, and involved in many cellular functions like “mRNA solicing”, “Tyrosine phosphorylation and enhanced Transcriptional activity”, “Transcription elongation”, “DNA damage repair”, etc.Ty Homolog-5 (SPT5)Analyzed by Co-Immunoprecipitation (Co-IP) and mass spectroscopy (MS), Kwak et al. found that ERH is associated with SPT5 elongation factor (Figure 2), which is the phosphorylation target of cyclin dependent kinase 9 (CDK9)/cyclin T1 and are important in regulating the elongation process (35). They further confirmed by co-immunoprecipitation that ERH can specifically bind to F-cell production 1 (FCP1), a phosphatase specific to the carboxyl-terminal domain of the large subunit of RNA polymerase II (RNAPII), stimulating transcription elongation (24, 35). However, the binding site has not been further confirmed. SPT5 is an overexpressing transcription elongation factors and stabilizes RNA polymerase II, orchestrates transcription cycles, and maintains the enhancer landscape (36, 37).Polymerase Delta Interaction Protein 46/S6K1 Aly/REF-Like TargetAnalyzed by YTH screening, Smyk et al. (38) demonstrated in 2006 that ERH interacted with polymerase δ interacting protein 46 or S6K1 Aly/REF-like target (PDIP46/SKAR, Figure 2), a protein partner of both the p50 subunit of DNA polymerase δ and p70 ribosomal protein S6 kinase 1 (S6K1). They examined the interaction between ERH and PDIP46/SKAR by glutathione S-transferase (GST) pull-down, co-IP, MS, and intracellular localizations assays. They further analyzed that 2 regions (274-368 and 379-421, C-terminal) of PDIP46/SKAR interact with ERH. They inferred that ERH connects PDIP46/SKAR with SPT5 and FCP1 and then play roles in coupling transcription to pre-mRNA processing. Blockade of binding to SPT-5 may become an entry point for ERH-targeted therapy.Cyclin Dependent Kinase Inhibitor 1A Interacting Zinc Finger Protein 1 (Ciz1)It is inferred that phosphorylation of CKII sites (Thr18 and Ser24) would disrupt the dimerization of ERH and then disrupt its interaction with other proteins (38). In 2008, using the YTH system, GST, and MS, Lukasik A et al. (39) found another molecular chaperone of ERH protein, the zinc finger protein 1 (Ciz1, Figure 2), that interacted with p21Cip1/Waf1. A region of 114 amino acids comprising residues 531–644 (contains a zine finger motif, 595-617) was shown to interact with ERH using YTH screening. They demonstrated by fluorescence co-localization assay that when Ciz1 and ERH are co-expressed in HeLa cells, Ciz1 could recruit ERH to the region of DNA replication. They indicated that ERH can block the action of Ciz1, and then reduce the expression of ERH inducted by DNA damage, which facilitates CDK-cyclinE-p21Cip1/Waf1 complex formation and enables the repair of DNA damage.Histocompatibility 19 Opposite Tumor SuppressorAnalyzed by co-IP and MS in 2011, ERH was shown to interact with HOTS, a tumor growth inhibitor encoded by H19 antisense transcript (Figure 2) (25). Onyango et al. immunoprecipitated the HOTS- Green fluorescent protein (GFP) by ERH antibodies, demonstrating that native ERH interacts with HOTS protein in HEK293 cells. HOTS is a tumor growth inhibitor, and the overexpression of HOTS inhibits Wilms, rhabdoid, rhabdomyosarcoma, and choriocarcinoma tumor cell growth (25).Small Nuclear Ribonucleoprotein D3 PolypeptideERH was shown using stable isotope labeling by amino acids in cell culture MS that it can interact with Sm protein SNRPD-3 (Figure 2) (9). Co-IP was used to confirm the interaction between ERH and SNRPD-3. ERH is required for the expression of mRNA splicing and the expression of centromere protein E (CENP-E). Xiao et al. (40) found that knockdown of ERH is cell cycle was blocked in the G1 phase in melanoma cells. This indicates that it might be a well target for cell cycle inhibition.Dishevelled, EGL-10 and Pleckstrin Domain Containing 1BIn 2015, Wu et al. (41) found that ERH can specifically bond with DEP domain containing 1B (DEPDC1B, Figure 2) (37). The DEP domain is a protein motif composed of nearly 100 amino acids found in three proteins (Dishevelled, EGL-10 and Pleckstrin), with cell membrane positioning, signal transduction and other functions. ERH was shown to intact with Scaffold attachment factor B1 (SAFB1) to reverse the inhibitory effect on the splicing kinase named Ser/Arg (SR)-rich splicing factor (SRSF) protein kinase 1 (SRPK1) exerted by SAFB1 in mammalian cells (42). DEPDC1B regulates the Rac1/PAK1 signaling and has an effect on the cell proliferation in prostate and pancreatic cancer cells (43, 44).PontinIt has been proven that ERH can combine with Pontin, a highly conserved AAA+ adenosine-triphosphate enzyme (ATPase) family member, to have an effect on serine-phosphorylated STAT3, regulating canonical tyrosine phosphorylation and enhancing transcriptional activity in gastric cancers (28). ERH can interact with thyroid hormone receptor-associated protein 3 (THRAP3), DiGeorge Syndrome Critical Region 8 (DGCR8), protein arginine methyltransferase 1 (PRMT1) and chromatin target of PRMT1 (CHTOP) proteins to regulated mRNA splicing (Figure 2) (45).Involved in PID-3, ERH-2, TOFU-6, and IFE-3 Small RNA ComplexERH is involved in many protein complexes, as supported by many research studies. For instance, Perez-Borrajero et al. (46) found that ERH was involved in the complex PETISCO (PID-3, ERH-2, TOFU-6, and IFE-3 small RNA complex), which is required for 21U RNA biogenesis. Another study showed that ERH is involved in the complex PICS (piRNA biogenesis and chromosome segregation, contains TOFU-6, PID-1, PICS-1, TOST-1 and ERH-2), which is concentrated at the perinuclear granule zone and engages in piDNA processing and chromosome segregation (Figure 2) (47).OthersERH is reported to interact with some other proteins (48), such as mediator complex subunit 31/comparative gene identification protein 125 (MED31/CGI-125), tumor protein p53 (TP53), 70 kDa heat shock protein 8 (heat shock protein, HSPA8) in Li-Fraumeni syndrome, but these results have not been confirmed in experiments.Functions of ERH GenePyrimidine MetabolismLiterature has shown that ERH plays an important role in biological processes such as pyrimidine biosynthesis, cell cycle regulation, and transcription inhibition (6). Enhanced mutation can promote the expression of carbamoyl phosphate synthetase II (CPSase), aspartate transcarbamoylase (ATCase), and dihydroorotase (DHOase) (CAD), a multifunctional enzyme involved in de novo pyrimidine biosynthesis (16). Interestingly, as Smyk et al. (38) speculated, if ERH is indeed involved in cell growth control, mutations in ERH can increase the effect of rudimentary mutations, resulting in enhanced wing truncation without directly affecting pyrimidine metabolism (38). No further studies have found whether ERH is directly or indirectly related to pyrimidine metabolism (Figure 3).FIGURE 3

Figure 3 Schematic diagram of functions ERH protein involved in cells. ERH protein can affect many molecules like MYC, SAFB1/2, and some pathways to have an effect on some functions on “tumorigenesis”, “mRNA splicing and processing”, “pyrimidine metabolism” etc.Transcriptional RepressorERH acts as a transcriptional repressor (34). ERH interacts with SAFB1 and alleviates the inhibition that the SAFB1/2 proteins exert on SRPK1, but it does not affect SAFB1/2 function in transcription (Figure 3).Cell Cycle RegulationAs the ERH protein can be phosphorylated by CKII, which is a kinase required at the G1/S and G2/M transitions, it is suggested that ERH protein may be involved in cell cycle regulation (38). Analyzed by luciferase reporter assay, Ishikawa et al. (41) demonstrated that miR-574-3p can bind to and regulate ERH to have an effect on the repair of DNA damage. It has been reported that ERH can interact with CIZ1 to initiate the process of DNA replication (39). CIZ1 is a zinc finger protein that can interact with p21, an important CDK2 inhibitor. As centromere-associated protein E (CENP-E), who degraded on mitosis exit and resynthesized in the next S-phase, can be inhibited by the combination of ERH and SNRPD-3. ERH has been shown to regulate the cell cycle in G2/M-phase (8, 9, 49). Cells lacking ERH do not complete DNA replication after release from a replication block (45). ERH is only weakly expressed in undivided hepatocyte cell lines, while it is expressed in large amounts in fibroblasts and hepatocarcinoma cell lines, indicating that ERH may have functions necessary for cell proliferation (7, 13).DNA Damage RepairIt was shown that loss of ERH attenuated UV-induced DNA damage repair in hepatocellular carcinoma (HCC) cells (50). Ishikawa et al. (41) discovered for the first time that in human lung adenocarcinoma, cerebral medulloblastoma, and astrocytoma cells, ERH is related to the repair of DNA damage when exposed to X-rays. ERH can control the expression of ATR (ataxia telangiectasia-mutated and Rad3-related) to regulate ATR-signaling pathway, which is a major mechanism by which cells respond to and repair replication-associated damage (45) (Figure 3).mRNA SplicingIt is demonstrated that ERH regulates mRNA splicing of CENP-E mRNA through interaction with the splice protein SNRPD3 (9); other studies have demonstrated that ERH can interact with thyroid hormone receptor-associated protein 3 (THRAP3), DGCR8, CHTOP and PRMT1 proteins, and most of these proteins are involved in mRNA splicing and processing (49) (Figure 3).MicroRNA Clustering Assists in Processing of Suboptimal MicroRNA HairpinsIt was reported in 2020 by Fang W et al. (51) that ERH protein is involved in the processing of suboptimal microRNA hairpin formation. SAFB can both dimerize and interact with ERH, and similarly, ERH can both dimerize and interact with Microprocessor. Together, these two proteins might mediate the association of two or more Microprocessors (51).MeiosisSome studies on the protein erh1 in yeast suggest some potential functions of ERH. Yamashita A et al. (52) found that S. pombe strains that are deficient in erh1 have significantly reduced tolerance to low temperature and participate in the Mmi1/DSR process, which causes the degradation of meiotic transcripts and is deleterious for meiosis (53, 54). In addition, Erh1 and its molecular chaperone can target and mediate histone 3 lysine 9 (H3K9) methyltransferase Clr4 to assemble facultative heterochromatin during meiosis (55, 56). Erh1 is proven to bind with protein Mmi1 to form a stoichiometric complex, called the Erh1-Mmi1 complex (EMC), to promote meiotic mRNA decay and facultative heterochromatin assembly (57). Mmi1 has a YTH domain, which can bind to target RNA, and the amino terminal end (95-122) of Mmi1 can bind to the processing complex of Erh1 and RNA, and finally form EMC (54), which is critical for nuclear retention of meiotic mRNAs (58).Erythroid DifferentiationERH gene was found (59) to be continuously regulated during erythropoiesis and its expression increased during differentiation, indicating that it plays an important role in red blood cell differentiation. But no further studies were conducted on this topic.Molecules that Regulate ERH ExpressionThe expression of ERH is affected by many factors. In 2014, Ishikawa et al. (41) found that when some malignant cells are exposed to X-rays, they can induce the expression of miR-574-3p, which suppresses the production of the ERH protein, resulting in the inhibition of cell growth. It was demonstrated by Sutherland J et al. (60) that Musashi-1 has the function of upregulating ERH expression. ERH is highly conserved and stable in its structure. It is an ideal therapeutic target for tumor-targeted therapeutic drugs.Is ERH a Good Target for Drug Design?Many studies suggest that ERH may be a good target for tumor therapy, and there are a few drugs that have been found to already target ERH for cancer therapy. However, it might cause a lot of side effects to inhibit the expression of ERH since it fulfills so many different roles. In 2015, Weng et al. (50) used AZD7762 (a CHK1 inhibitor) to inhibit the ERH-ATR axis, and they found that AZD7762 induces S-phase arrest and sensitizes HCC cells to doxorubicin, a well-studied chemotherapy for treating HCC4. They also observed strong inhibition in the growth of HCC xenografts in mice treated with a combination of doxorubicin plus AZD7762 (50). In 2021, Park et al. (61) confirmed that ERH augmented anthocyanins isolated from Meoru (AIMs)-induced caspase-dependent apoptosis by activating caspase-3 and -9. They discussed the relationship between augmented expression of ERH and the therapeutic effects of AIM (61). Whether it is because of the side effects, or whether there is no drug that can inhibit ERH, still needs further confirmation. According to the existing research results, by affecting the CKII phosphorylation sites of ERH gene, it may affect the binding of ERH protein to its protein partners, thereby affecting the further functions to inhibit the development of malignancies.ConclusionThe ERH gene encodes a nuclear protein that is highly conserved in animals and plants. Recent studies have shown that ERH plays an adjunct role in promoting tumorigenesis in a variety of malignancies. ERH protein can be combined with a variety of proteins, affecting cell proliferation, cell cycle, DNA repair and other functions of different directions. The ERH gene plays an important role in the occurrence and development of malignant tumors, however, there are only a few drugs that target and regulate the expression of ERH by now. For the treatment of the majority of cancer patients, more targeted drugs to inhibit ERH expression should be developed.Author ContributionsConceptualization: KP, M-LL, Z-SC and C-HH. Literature review: LH, Z-DS, BC, Y-YM, HX and DP. Quality Control: Z-SC and C-HH. Language editing: HF. Writing—original draft preparation: KP, M-LL, HF. Writing—review and editing: Z-SC and C-HH. Supervision, Z-SC and C-HH. All authors contributed to the article and approved the submitted version.FundingNational Natural Science Fund (82004100, 81774089); Jiangsu Maternal and Child Health Association Project (FYX202026); Jiangsu Province key research and development program (BE2020758, BE2019637); Xuzhou Medical University Excellent Talent Fund Project (XYFY2020016, XYFY2020026); Jiangsu Province, the medical innovation team (CXTDA2017048).Conflict of InterestThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Publisher’s NoteAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.AcknowledgmentsWe would like to thank UniWinSci for providing the English editing service for this article.References 1. Siegel RL, Miller KD. Cancer Statistic. CA Cancer J Clin (2022) 72:7–33. doi: 10.3322/caac.21708PubMed Abstract | CrossRef Full Text | Google Scholar 2. Kang Y, Jin Y, Li Q, Yuan X. Advances in Lung Cancer Driver Genes Associated With Brain Metastasis. Front Oncol (2020) 10:606300. doi: 10.3389/fonc.2020.606300PubMed Abstract | CrossRef Full Text | Google Scholar 3. Danesi R, Fogli S, Indraccolo S, Del Re M, Dei Tos AP, Leoncini L, et al. Druggable Targets Meet Oncogenic Drivers: Opportunities and Limitations of Target-Based Classification of Tumors and the Role of Molecular Tumor Boards. ESMO Open (2021) 6:100040. doi: 10.1016/j.esmoop.2020.100040PubMed Abstract | CrossRef Full Text | Google Scholar 4. Chen ZY, Hsieh YM, Huang CC, Tsai CC. Inhibitory Effects of Probiotic Lactobacillus on the Growth of Human Colonic Carcinoma Cell Line HT-29. Molecules (2017) 22(1):107. doi: 10.3390/molecules22010107CrossRef Full Text | Google Scholar 5. Chiang CM, Chang YJ, Wu JY, Chang TS. Production and Anti-Melanoma Activity of Methoxyisoflavones From the Biotransformation of Genistein by Two Recombinant Escherichia Coli Strains. Molecules (2017) 22(1):87. doi: 10.3390/molecules22010087CrossRef Full Text | Google Scholar 6. Jin T, Guo F, Serebriiskii IG, Howard A, Zhang YZ. A 1.55 A Resolution X-Ray Crystal Structure of HEF2/ERH and Insights Into Its Transcriptional and Cell-Cycle Interaction Networks. Proteins (2007) 68:427–37. doi: 10.1002/prot.21343PubMed Abstract | CrossRef Full Text | Google Scholar 7. Zafrakas M, Losen I, Knuchel R, Dahl E. Enhancer of the Rudimentary Gene Homologue (ERH) Expression Pattern in Sporadic Human Breast Cancer and Normal Breast Tissue. BMC Cancer (2008) 8:145. doi: 10.1186/1471-2407-8-145PubMed Abstract | CrossRef Full Text | Google Scholar 8. Fujimura A, Kishimoto H, Yanagisawa J, Kimura K. Enhancer of Rudimentary Homolog (ERH) Plays an Essential Role in the Progression of Mitosis by Promoting Mitotic Chromosome Alignment. Biochem Biophys Res Commun (2012) 423:588–92. doi: 10.1016/j.bbrc.2012.06.018PubMed Abstract | CrossRef Full Text | Google Scholar 9. Weng MT, Lee JH, Wei SC, Li Q, Shahamatdar S, Hsu D, et al. Evolutionarily Conserved Protein ERH Controls CENP-E mRNA Splicing and Is Required for the Survival of KRAS Mutant Cancer Cells. Proc Natl Acad Sci USA (2012) 109:E3659–67. doi: 10.1073/pnas.1207673110PubMed Abstract | CrossRef Full Text | Google Scholar 10. Falk DR, Mccaughin G, Cogley T. A Genetic and Biochemical Analysis of the Temperature Sensitive, Normal-Winged Alleles of the Rudimentary Locus of Drosophila Melanogaster. Genetics (1977) 86:765–77. doi: 10.1093/genetics/86.4.765PubMed Abstract | CrossRef Full Text | Google Scholar 11. Fausto-Sterling A, Hsieh L. Studies on the Female-Sterile Mutant Rudimentary of Drosophila Melanogaster. 1. An Analysis of the Rudimentary Wing Phenotype. Dev Biol (1976) 51:269–81. doi: 10.1016/0012-1606(76)90143-3PubMed Abstract | CrossRef Full Text | Google Scholar 12. Isomura M, Okui K, Fujiwara T, Shin S, Nakamura Y. Cloning and Mapping of a Novel Human cDNA Homologous to DROER, the Enhancer of the Drosophila Melanogaster Rudimentary Gene. Genomics (1996) 32:125–7. doi: 10.1006/geno.1996.0086PubMed Abstract | CrossRef Full Text | Google Scholar 13. Gelsthorpe M, Pulumati M, Mccallum C, Dang-Vu K, Tsubota SI. The Putative Cell Cycle Gene, Enhancer of Rudimentary, Encodes a Highly Conserved Protein Found in Plants and Animals. Gene (1997) 186:189–95. doi: 10.1016/S0378-1119(96)00701-9PubMed Abstract | CrossRef Full Text | Google Scholar 14. Schneider K, Wells B, Dolan L, Roberts K. Structural and Genetic Analysis of Epidermal Cell Differentiation in Arabidopsis Primary Roots. Development (1997) 124:1789–98. doi: 10.1242/dev.124.9.1789PubMed Abstract | CrossRef Full Text | Google Scholar 15. Wang W, Yang X, Tangchaiburana S, Ndeh R, Markham JE, Tsegaye Y, et al. An Inositolphosphorylceramide Synthase Is Involved in Regulation of Plant Programmed Cell Death Associated With Defense in Arabidopsis. Plant Cell (2008) 20:3163–79. doi: 10.1105/tpc.108.060053PubMed Abstract | CrossRef Full Text | Google Scholar 16. Wojcik E, Murphy AM, Fares H, Dang-Vu K, Tsubota SI. Enhancer of Rudimentaryp1, E(R)P1, A Highly Conserved Enhancer of the Rudimentary Gene. Genetics (1994) 138:1163–70. doi: 10.1093/genetics/138.4.1163PubMed Abstract | CrossRef Full Text | Google Scholar 17. Krzyzanowski MK, Kozlowska E, Kozlowski P. Identification and Functional Analysis of the Erh1(+) Gene Encoding Enhancer of Rudimentary Homolog From the Fission Yeast Schizosaccharomyces Pombe. PloS One (2012) 7:e49059. doi: 10.1371/journal.pone.0049059PubMed Abstract | CrossRef Full Text | Google Scholar 18. Arai R, Kukimoto-Niino M, Uda-Tochio H, Morita S, Uchikubo-Kamo T, Akasaka R, et al. Crystal Structure of an Enhancer of Rudimentary Homolog (ERH) at 2.1 Angstroms Resolution. Protein Sci (2005) 14:1888–93. doi: 10.1110/ps.051484505PubMed Abstract | CrossRef Full Text | Google Scholar 19. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, et al. The Protein Data Bank. Nucleic Acids Research (2000) 28:235–42.PubMed Abstract | Google Scholar 20. Sehnal D, Bittrich S, Deshpande M, Svobodová R, Berka K, Bazgier V, et al. Mol* Viewer: Modern Web App for 3D Visualization and Analysis of Large Biomolecular structures. Nucleic Acids Res (2021) 49(W1):W431–37. doi: 10.1136/bmjopen-2019-036563PubMed Abstract | CrossRef Full Text | Google Scholar 21. Wan C, Tempel W, Liu ZJ, Wang BC, Rose RB. Structure of the Conserved Transcriptional Repressor Enhancer of Rudimentary Homolog. Biochemistry (2005) 44:5017–23. doi: 10.1021/bi047785wPubMed Abstract | CrossRef Full Text | Google Scholar 22. Jin T, Howard A, Golemis EA, Wang Y, Zhang YZ. Overproduction, Purification, Crystallization and Preliminary X-Ray Diffraction Studies of the Human Transcription Repressor ERH. Acta Crystallogr Sect F Struct Biol Cryst Commun (2005) 61:531–3. doi: 10.1107/S1744309105012388PubMed Abstract | CrossRef Full Text | Google Scholar 23. Pogge Von Strandmann E, Senkel S, Ryffel GU. ERH (Enhancer of Rudimentary Homologue), a Conserved Factor Identical Between Frog and Human, is a Transcriptional Repressor. Biol Chem (2001) 382:1379–85. doi: 10.1515/BC.2001.170PubMed Abstract | CrossRef Full Text | Google Scholar 24. Amente S, Napolitano G, Licciardo P, Monti M, Pucci P, Lania L, et al. Identification of Proteins Interacting With the RNAPII FCP1 Phosphatase: FCP1 Forms a Complex With Arginine Methyltransferase PRMT5 and It Is a Substrate for PRMT5-Mediated Methylation. FEBS Lett (2005) 579:683–9. doi: 10.1016/j.febslet.2004.12.045PubMed Abstract | CrossRef Full Text | Google Scholar 25. Onyango P, Feinberg AP. A Nucleolar Protein, H19 Opposite Tumor Suppressor (HOTS), Is a Tumor Growth Inhibitor Encoded by a Human Imprinted H19 Antisense Transcript. Proc Natl Acad Sci USA (2011) 108:16759–64. doi: 10.1073/pnas.1110904108PubMed Abstract | CrossRef Full Text | Google Scholar 26. Pang K, Lv Q, Ning SY, Hao L, Shi ZD, Zang GH, et al. ERH Is Up-Regulated in Bladder Cancer and Regulates the Proliferation and Apoptosis of T24 Bladder Cancer Cells. Int J Of Clin And Exp Med (2017) 10:15269–77.Google Scholar 27. Pang K, Zhang Z, Hao L, Shi Z, Chen B, Zang G, et al. The ERH Gene Regulates Migration and Invasion in 5637 and T24 Bladder Cancer Cells. BMC Cancer (2019) 19:225. doi: 10.1186/s12885-019-5423-9PubMed Abstract | CrossRef Full Text | Google Scholar 28. Balic JJ, Garama DJ, Saad MI, Yu L, West AC, West AJ, et al. Serine-Phosphorylated STAT3 Promotes Tumorigenesis via Modulation of RNA Polymerase Transcriptional Activity. Cancer Res (2019) 79:5272–87. doi: 10.1158/0008-5472.CAN-19-0974PubMed Abstract | CrossRef Full Text | Google Scholar 29. Jones SA, Jenkins BJ. Recent Insights Into Targeting the IL-6 Cytokine Family in Inflammatory Diseases and Cancer. Nat Rev Immunol (2018) 18:773–89. doi: 10.1038/s41577-018-0066-7PubMed Abstract | CrossRef Full Text | Google Scholar 30. Yang J, Liao X, Agarwal MK, Barnes L, Auron PE, Stark GR. Unphosphorylated STAT3 Accumulates in Response to IL-6 and Activates Transcription by Binding to NFkappaB. Genes Dev (2007) 21:1396–408. doi: 10.1101/gad.1553707PubMed Abstract | CrossRef Full Text | Google Scholar 31. Pang K, Han C, Hao L, Shi Z. ERH Gene Targets NFKB1 Gene and Regulating NF-Kappa B Pathway to Enhances Epithelial-Mesenchymal Transition Related Migration and Invasion of Bladder Cancer T24 Cells. Int J Of Urol (2019), 5–5. WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA.Google Scholar 32. Pang K, Hao L, Shi Z, Chen B, Pang H, Dong Y, et al. Comprehensive Gene Expression Analysis After ERH Gene Knockdown in Human Bladder Cancer T24 Cell Lines. Gene (2020) 738:144475. doi: 10.1016/j.gene.2020.144475PubMed Abstract | CrossRef Full Text | Google Scholar 33. Zhang D, Chu YJ, Song KJ, Chen YL, Liu W, Lv T, et al. Knockdown of Enhancer of Rudimentary Homolog Inhibits Proliferation and Metastasis in Ovarian Cancer by Regulating Epithelial-Mesenchymal Transition. BioMed Pharmacother (2020) 125:109974. doi: 10.1016/j.biopha.2020.109974PubMed Abstract | CrossRef Full Text | Google Scholar 34. Pogge V Strandmann E, Senkel S, Ryffel GU. Ectopic Pigmentation in Xenopus in Response to DCoH/PCD, the Cofactor of HNF1 Transcription Factor/Pterin-4alpha-Carbinolamine Dehydratase. Mech Dev (2000) 91:53–60. doi: 10.1016/S0925-4773(99)00269-5PubMed Abstract | CrossRef Full Text | Google Scholar 35. Kwak YT, Guo J, Prajapati S, Park KJ, Surabhi RM, Miller B, et al. Methylation of SPT5 Regulates its Interaction With RNA Polymerase II and Transcriptional Elongation Properties. Mol Cell (2003) 11:1055–66. doi: 10.1016/S1097-2765(03)00101-1PubMed Abstract | CrossRef Full Text | Google Scholar 36. Han J, Tam K, Tam C, Hollis RP, Kohn DB. Improved Lentiviral Vector Titers From a Multi-Gene Knockout Packaging Line. Mol Ther Oncolytics (2021) 23:582–92. doi: 10.1016/j.omto.2021.11.012PubMed Abstract | CrossRef Full Text | Google Scholar 37. Wu D, Zhu X, Jimenez-Cowell K, Mold AJ, Sollecito CC, Lombana N, et al. Identification of the GTPase-Activating Protein DEP Domain Containing 1B (DEPDC1B) as a Transcriptional Target of Pitx2. Exp Cell Res (2015) 333:80–92. doi: 10.1016/j.yexcr.2015.02.008PubMed Abstract | CrossRef Full Text | Google Scholar 38. Smyk A, Szuminska M, Uniewicz KA, Graves LM, Kozlowski P. Human Enhancer of Rudimentary Is a Molecular Partner of PDIP46/SKAR, A Protein Interacting With DNA Polymerase Delta and S6K1 and Regulating Cell Growth. FEBS J (2006) 273:4728–41. doi: 10.1111/j.1742-4658.2006.05477.xPubMed Abstract | CrossRef Full Text | Google Scholar 39. Lukasik A, Uniewicz KA, Kulis M, Kozlowski P. Ciz1, a P21 Cip1/Waf1-Interacting Zinc Finger Protein and DNA Replication Factor, Is a Novel Molecular Partner for Human Enhancer of Rudimentary Homolog. FEBS J (2008) 275:332–40. doi: 10.1111/j.1742-4658.2007.06203.xPubMed Abstract | CrossRef Full Text | Google Scholar 40. Martin LB, Liebl AL, Kilvitis HJ. Covariation in Stress and Immune Gene Expression in a Range Expanding Bird. Gen Comp Endocrinol (2015) 211:14–9. doi: 10.1016/j.ygcen.2014.11.001PubMed Abstract | CrossRef Full Text | Google Scholar 41. Ishikawa K, Ishikawa A, Shoji Y, Imai T. A Genotoxic Stress-Responsive miRNA, miR-574-3p, Delays Cell Growth by Suppressing the Enhancer of Rudimentary Homolog Gene In Vitro. Int J Mol Sci (2014) 15:2971–90. doi: 10.3390/ijms15022971PubMed Abstract | CrossRef Full Text | Google Scholar 42. Drakouli S, Lyberopoulou A, Papathanassiou M, Mylonis I, Georgatsou E. Enhancer of Rudimentary Homologue Interacts With Scaffold Attachment Factor B at the Nuclear Matrix to Regulate SR Protein Phosphorylation. FEBS J (2017) 284:2482–500. doi: 10.1111/febs.14141PubMed Abstract | CrossRef Full Text | Google Scholar 43. Li Z, Wang Q, Peng S, Yao K, Chen J, Tao Y, et al. The Metastatic Promoter DEPDC1B Induces Epithelial-Mesenchymal Transition and Promotes Prostate Cancer Cell Proliferation via Rac1-PAK1 Signaling. Clin Transl Med (2020) 10:e191. doi: 10.1002/ctm2.191PubMed Abstract | CrossRef Full Text | Google Scholar 44. Zhang S, Shi W, Hu W, Ma D. DEP Domain-Containing Protein 1b (DEPDC1B) Promotes Migration and Invasion in Pancreatic Cancer Through the Rac1/PAK1-LIMK1-Cofilin1 Signaling Pathway. Onco Targets Ther (2020) 13:1481–96. doi: 10.2147/OTT.S229055PubMed Abstract | CrossRef Full Text | Google Scholar 45. Kavanaugh G, Zhao R, Guo Y, Mohni KN, Glick G, Lacy ME, et al. Enhancer of Rudimentary Homolog Affects the Replication Stress Response Through Regulation of RNA Processing. Mol Cell Biol (2015) 35:2979–90. doi: 10.1128/MCB.01276-14PubMed Abstract | CrossRef Full Text | Google Scholar 46. Oehl-Jaschkowitz B, Vanakker OM, De Paepe A, Menten B, Martin T, Weber G, et al. Deletions in 14q24.1q24.3 Are Associated With Congenital Heart Defects, Brachydactyly, and Mild Intellectual Disability. Am J Med Genet A (2014) 164a:620–6. doi: 10.1002/ajmg.a.36321PubMed Abstract | CrossRef Full Text | Google Scholar 47. Zeng C, Weng C, Wang X, Yan YH, Li WJ, Xu D, et al. Functional Proteomics Identifies a PICS Complex Required for piRNA Maturation and Chromosome Segregation. Cell Rep (2019) 27:3561–3572.e3. doi: 10.1016/j.celrep.2019.05.076PubMed Abstract | CrossRef Full Text | Google Scholar 48. Gelsthorpe ME, Tan Z, Phillips A, Eissenberg JC, Miller A, Wallace J, et al. Regulation of the Drosophila Melanogaster Protein, Enhancer of Rudimentary, by Casein Kinase II. Genetics (2006) 174:265–70. doi: 10.1534/genetics.106.061465PubMed Abstract | CrossRef Full Text | Google Scholar 49. Weng MT, Luo J. The Enigmatic ERH Protein: Its Role in Cell Cycle, RNA Splicing and Cancer. Protein Cell (2013) 4:807–12. doi: 10.1007/s13238-013-3056-3PubMed Abstract | CrossRef Full Text | Google Scholar 50. Weng MT, Tung TH, Lee JH, Wei SC, Lin HL, Huang YJ, et al. Enhancer of Rudimentary Homolog Regulates DNA Damage Response in Hepatocellular Carcinoma. Sci Rep (2015) 5:9357. doi: 10.1038/srep09357PubMed Abstract | CrossRef Full Text | Google Scholar 51. Fang W, Bartel DP. MicroRNA Clustering Assists Processing of Suboptimal MicroRNA Hairpins Through the Action of the ERH Protein. Mol Cell (2020) 78:289–302.e6. doi: 10.1016/j.molcel.2020.01.026PubMed Abstract | CrossRef Full Text | Google Scholar 52. Yamashita A, Takayama T, Iwata R, Yamamoto M. A Novel Factor Iss10 Regulates Mmi1-Mediated Selective Elimination of Meiotic Transcripts. Nucleic Acids Res (2013) 41:9680–7. doi: 10.1093/nar/gkt763PubMed Abstract | CrossRef Full Text | Google Scholar 53. Harigaya Y, Tanaka H, Yamanaka S, Tanaka K, Watanabe Y, Tsutsumi C, et al. Selective Elimination of Messenger RNA Prevents an Incidence of Untimely Meiosis. Nature (2006) 442:45–50. doi: 10.1038/nature04881PubMed Abstract | CrossRef Full Text | Google Scholar 54. Hazra D, Andric V, Palancade B, Rougemaille M, Graille M. Formation of S. Pombe Erh1 Homodimer Mediates Gametogenic Gene Silencing and Meiosis Progression. Sci Rep (2020) 10:1034. doi: 10.1038/s41598-020-57872-4PubMed Abstract | CrossRef Full Text | Google Scholar 55. Tashiro S, Asano T, Kanoh J, Ishikawa F. Transcription-Induced Chromatin Association of RNA Surveillance Factors Mediates Facultative Heterochromatin Formation in Fission Yeast. Genes Cells (2013) 18:327–39. doi: 10.1111/gtc.12038PubMed Abstract | CrossRef Full Text | Google Scholar 56. Zofall M, Yamanaka S, Reyes-Turcu FE, Zhang K, Rubin C, Grewal SI. RNA Elimination Machinery Targeting Meiotic mRNAs Promotes Facultative Heterochromatin Formation. Science (2012) 335:96–100. doi: 10.1126/science.1211651PubMed Abstract | CrossRef Full Text | Google Scholar 57. Sugiyama T, Thillainadesan G, Chalamcharla VR, Meng Z, Balachandran V, Dhakshnamoorthy J, et al. Enhancer of Rudimentary Cooperates With Conserved RNA-Processing Factors to Promote Meiotic mRNA Decay and Facultative Heterochromatin Assembly. Mol Cell (2016) 61:747–59. doi: 10.1016/j.molcel.2016.01.029PubMed Abstract | CrossRef Full Text | Google Scholar 58. Xie G, Vo TV, Thillainadesan G, Holla S, Zhang B, Jiang Y, et al. A Conserved Dimer Interface Connects ERH and YTH Family Proteins to Promote Gene Silencing. BMC Cancer (2019) 10:251. doi: 10.1038/s41467-018-08273-9CrossRef Full Text | Google Scholar 59. Da Cunha AF, Brugnerotto AF, Duarte AS, Lanaro C, Costa GG, Saad ST, et al. Global Gene Expression Reveals a Set of New Genes Involved in the Modification of Cells During Erythroid Differentiation. Cell Prolif (2010) 43:297–309. doi: 10.1111/j.1365-2184.2010.00679.xPubMed Abstract | CrossRef Full Text | Google Scholar 60. Sutherland JM, Sobinoff AP, Fraser BA, Redgrove KA, Davidson TL, Siddall NA, et al. RNA Binding Protein Musashi-1 Directly Targets Msi2 and Erh During Early Testis Germ Cell Development and Interacts With IPO5 Upon Translocation to the Nucleus. FASEB J (2015) 29:2759–68. doi: 10.1096/fj.14-265868PubMed Abstract | CrossRef Full Text | Google Scholar 61. Hammond ER, Tummala R, Berglind A, Syed F, Wang X, Desta B, et al. Study Protocol for the International Systemic Lupus Erythematosus Prospective Observational Cohort Study (SPOCS): Understanding Lupus and the Role of Type I Interferon Gene Signature. BMJ Open (2020) 10:e036563. doi: 10.1136/bmjopen-2019-036563PubMed Abstract | CrossRef Full Text | Google ScholarKeywords: enhancer of rudimentary homolog (ERH) gene, oncogenesis factor, protein partner, transcription factor, tumor-targeted therapyCitation: Pang K, Li M-l, Hao L, Shi Z-d, Feng H, Chen B, Ma Y-y, Xu H, Pan D, Chen Z-S and Han C-h (2022) ERH Gene and Its Role in Cancer Cells. Front. Oncol. 12:900496. doi: 10.3389/fonc.2022.900496Received: 20 March 2022; Accepted: 05 April 2022;Published: 23 May 2022.Edited by:Fei Chen, Wayne State University, United StatesReviewed by:Yiran Qiu, Stony Brook University, United StatesChitra Thakur, Stony Brook University, United StatesCopyright © 2022 Pang, Li, Hao, Shi, Feng, Chen, Ma, Xu, Pan, Chen and Han. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*Correspondence: Cong-hui Han, 479920288@qq.com; Zhe-Sheng Chen, chenz@stjohns.edu†These authors have contributed equally to this work and share first authorship Disclaimer:

All claims expressed in this article are solely those of the authors and

do not necessarily represent those of their affiliated organizations, or

those of the publisher, the editors and the reviewers. Any product that

may be evaluated in this article or claim that may be made by its

manufacturer is not guaranteed or endorsed by the publisher.

Footer Guidelines Author guidelinesEditor guidelinesPolicies and publication ethicsFee policy Explore ArticlesResearch Topics Journals Outreach Frontiers Forum Frontiers Policy Labs Frontiers for Young Minds Connect Help centerEmails and alerts Contact us SubmitCareer opportunities Follow us © 2024 Frontiers Media S.A. All rights reserved Privacy policy | Terms and conditions