Super enhancers at the miR-146a and miR-155 genes contribute to self-regulation of inflammation
Super enhancers at the miR-146a and miR-155 genes contribute to self-regulation of inflammation
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miR-146a 和 miR-155 基因的超级增强子有助于炎症的自我调节
DOI：
10.1016/j.bbagrm.2016.02.004
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发表时间：
2016-04-01
影响因子：
4.7
通讯作者：
Yang, Tianlun
中科院分区：
文献类型：
--
作者：
Duan, Qiong;Mao, Xiaoxiao;Yang, Tianlun
炎症反应对于宿主防御和修复是必不可少的，并且需要严格的调节，因为过度和持续的炎症反应是有害的。我们最近发现炎症基因转录调控的一个普遍但关键的机制是由NF-κ B、布罗莫结构域和末端外（BET）蛋白介导的超级增强子的形成所控制。鉴于microRNA转录与mRNA的转录机制相似，我们假设炎症microRNA的转录可能是NF-κ B和BET布罗莫结构域依赖的。在本研究中，我们证实了炎症刺激改变了人脐静脉内皮细胞（HUVEC）的microRNA谱。在这些microRNA中，miR-146 a和miR-155（两种公认的炎性microRNA）均通过NF-κ B和BET布罗莫结构域抑制在转录水平下调。为了探究这一机制，我们分析了ChIP-seq数据，发现NF-κ B B、BRD 4和RNA POL II快速分布在miR-146 a和miR-155的上游区域，更重要的是介导了驱动miR-146 a和miR-155转录的超级增强子的形成。这些由超级增强子驱动的microRNA转录反过来通过靶向炎症介质下调体外和体内典型炎症基因的表达。这一新的发现表明宿主如何在转录和转录后水平上自我调节炎症基因的表达，以确保宿主炎症反应的适当水平。(C)© 2016 Elsevier B. V.版权所有。
Inflammatory response is essential to host defense and repair, and requires tight regulation as excessive and constant inflammatory response is deleterious. We recently identified that one of the general but key mechanisms for inflammatory gene transcription regulation is controlled by the formation of super enhancers mediated by NF-kappa B, and bromodomain and extraterminal (BET) proteins.Given that microRNA transcription shares a similar mechanism to mRNA, we assume that the inflammatory microRNAs transcription could be NF-kappa B and BET bromodomain dependent. In the present study, we confirmed that inflammatory stimuli changed human umbilical vein endothelial cells (HUVEC) microRNA profile. Among these microRNAs, miR-146a and miR-155, two well-established inflammatory microRNAs, are both down-regulated at transcriptional level by NF-kappa B and BET bromodomain inhibition. To pursue this mechanism, we analyzed the ChIP-seq data and found that NF-kappa B, BRD4 and RNA POL II were rapidly distributed at the upstream regions of miR-146a and miR-155, and more importantly mediated the formation of the super enhancers that drive miR-146a and miR-155 transcription. These microRNAs transcription driven by super enhancers in turn downregulate both in vitro and in vivo canonical inflammatory genes expression through targeting inflammatory mediators. This novel finding demonstrated how the host self-regulates inflammatory genes expression at both transcriptional and post-transcriptional level to ensure the appropriate level of the host inflammatory response. (C) 2016 Elsevier B.V. All rights reserved.