Gao Ming, Liu Yun, Chen Yue, Yin Chunyang, Chen Jane-Jane, Liu Sijin
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
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.
Free Radic Biol Med. 2016 Mar;92:39-49. doi: 10.1016/j.freeradbiomed.2016.01.005. Epub 2016 Jan 12.
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.
核因子（红系衍生2）样2（Nrf2）是通过靶向许多抗应激反应基因来保护细胞免受应激的关键调节因子。最近的证据还表明，Nrf2部分通过靶向微小RNA（miRNA）发挥作用。然而，对于Nrf2通过miRNA依赖机制介导的细胞保护作用的了解在很大程度上还不清楚。在本研究中，我们鉴定了一种直接被Nrf2靶向的miRNA，即miR-214，并证明了miR-214在红系细胞中对辐射、过量铁和砷（As）暴露所产生的氧化应激具有保护作用。miR-214的表达在其启动子区域通过一个典型的抗氧化反应元件（ARE）被Nrf2转录抑制，并且这种抑制是依赖活性氧（ROS）的。Nrf2对miR-214的抑制可通过两种方式拮抗红系细胞中氧化应激诱导的细胞死亡。首先，miR-214直接靶向ATF4，ATF4是一种参与抗应激反应的关键转录因子，miR-214的下调解除了对ATF4翻译的抑制，导致ATF4蛋白含量增加。其次，miR-214能够通过靶向EZH2来防止细胞死亡，EZH2是PRC2复合物的催化核心成分，负责组蛋白3（H3）赖氨酸27（K27）的三甲基化反应（H3K27me3），由此As诱导的miR-214减少导致整体H3K27me3水平升高以及促凋亡基因Bim的过表达受损。miR-214下游的这两条途径协同合作以拮抗氧化应激时的红系细胞死亡。我们的综合数据揭示了miR-214信号通路在红系细胞中对氧化应激的保护作用，也为Nrf2介导的细胞保护机制提供了新的线索。
