title: miR-214 protects erythroid cells against oxidative stress by targeting ATF4 and EZH2.
abstract: Nuclear factor (erythroid-derived 2) like 2 (Nrf2) is a key regulator in protecting cells against stress by targeting many anti-stress response genes. Recent evidence also reveals that Nrf2 functions partially by targeting mircroRNAs (miRNAs). However, the understanding of Nrf2-mediated cytoprotection through miRNA-dependent mechanisms is largely unknown. In the current study, we identified a direct Nrf2 targeting miRNA, miR-214, and demonstrated a protective role of miR-214 in erythroid cells against oxidative stresses generated by radiation, excess iron and arsenic (As) exposure. miR-214 expression was transcriptionally repressed by Nrf2 through a canonical antioxidant response element (ARE) within its promoter region, and this repression is ROS-dependence. The suppression of miR-214 by Nrf2 could antagonize oxidative stress-induced cell death in erythroid cells by two ways. First, miR-214 directly targeted ATF4, a crucial transcriptional factor involved in anti-stress responses, down regulation of miR-214 releases the repression of ATF4 translation and leads to increased ATF4 protein content. Second, miR-214 was able to prevent cell death by targeting EZH2, the catalytic core component of PRC2 complex that is responsible for tri-methylation reaction at lysine 27 (K27) of histone 3 (H3) (H3K27me3), by which As-induced miR-214 reduction resulted in an increased global H3K27me3 level and a compromised overexpression of a pro-apoptotic gene Bim. These two pathways downstream of miR-214 synergistically cooperated to antagonize erythroid cell death upon oxidative stress. Our combined data revealed a protective role of miR-214 signaling in erythroid cells against oxidative stress, and also shed new light on Nrf2-mediated cytoprotective machinery.
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences and Anhui Province, Hefei, Anhui 230031, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors.forename: Chunyang
authors.initials: C
authors.lastname: Yin
authors.affiliation: Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Jane-Jane
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China. Electronic address: sjliu@rcees.ac.cn.
authors.forename: Sijin
authors.initials: S
authors.lastname: Liu
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis*; D061745:Antioxidant Response Elements / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001151:Arsenic / Q000633:toxicity; D019610:Cytoprotection / Q000187:drug effects; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000096:biosynthesis; D041905:Erythroid Cells / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007501:Iron / Q000633:toxicity; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011827:Radiation
chemical_list: C497109:ATF4 protein, human; C547397:MIRN214 microRNA, human; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D051701:Activating Transcription Factor 4; D007501:Iron; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D001151:Arsenic
keywords: ATF4; EZH2; Erythroid cells; Nrf2; miR-214