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miR-146a和miR-155基因处的超级增强子有助于炎症的自我调节。

Super enhancers at the miR-146a and miR-155 genes contribute to self-regulation of inflammation.

作者信息

Duan Qiong, Mao Xiaoxiao, Xiao Yi, Liu Zhenzhen, Wang Yangui, Zhou Haoyang, Zhou Zhengxiang, Cai Jinxing, Xia Ke, Zhu Qubo, Qi Jun, Huang He, Plutzky Jorge, Yang Tianlun

机构信息

Cardiovascular Division, Xiangya Hospital, Central South University, Changsha, China.

Cardiovascular Division, Xiangya Hospital, Central South University, Changsha, China; Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

出版信息

Biochim Biophys Acta. 2016 Apr;1859(4):564-71. doi: 10.1016/j.bbagrm.2016.02.004. Epub 2016 Feb 5.

Abstract

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-κB, 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-κB 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 downregulated at transcriptional level by NF-κB and BET bromodomain inhibition. To pursue this mechanism, we analyzed the ChIP-seq data and found that NF-κB, 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.

摘要

炎症反应对于宿主防御和修复至关重要,且需要严格调控,因为过度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核因子κB(NF-κB)、溴结构域和额外末端结构域(BET)蛋白介导的超级增强子的形成所控制。鉴于微小RNA转录与信使核糖核酸(mRNA)具有相似机制,我们推测炎症性微小RNA的转录可能依赖于NF-κB和BET溴结构域。在本研究中,我们证实炎症刺激改变了人脐静脉内皮细胞(HUVEC)的微小RNA谱。在这些微小RNA中,两个公认的炎症性微小RNA,即miR-146a和miR-155,在转录水平上均因NF-κB和BET溴结构域的抑制而下调。为探究此机制,我们分析了染色质免疫沉淀测序(ChIP-seq)数据,发现NF-κB、BRD4和RNA聚合酶II(RNA POL II)迅速分布于miR-146a和miR-155的上游区域,更重要的是介导了驱动miR-146a和miR-155转录的超级增强子的形成。由超级增强子驱动的这些微小RNA转录反过来通过靶向炎症介质在体外和体内下调经典炎症基因的表达。这一新发现揭示了宿主如何在转录和转录后水平自我调节炎症基因的表达,以确保宿主炎症反应处于适当水平。

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