title: Super enhancers at the miR-146a and miR-155 genes contribute to self-regulation of inflammation.
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.
authors: Cardiovascular Division, Xiangya Hospital, Central South University, Changsha, China.
authors: Qiong
authors: Q
authors: Duan
authors: Cardiovascular Division, Xiangya Hospital, Central South University, Changsha, China; Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
authors: Xiaoxiao
authors: X
authors: Mao
authors: Cardiovascular Division, Xiangya Hospital, Central South University, Changsha, China.
authors: Yi
authors: Y
authors: Xiao
authors: Cardiovascular Division, Xiangya Hospital, Central South University, Changsha, China.
authors: Zhenzhen
authors: Z
authors: Liu
authors: Cardiovascular Division, Xiangya Hospital, Central South University, Changsha, China; Department of Gerontology, The People's Hospital of Hunan Province, Changsha, China.
authors: Yangui
authors: Y
authors: Wang
authors: Cardiovascular Division, Xiangya Hospital, Central South University, Changsha, China.
authors: Haoyang
authors: H
authors: Zhou
authors: Cardiovascular Division, Xiangya Hospital, Central South University, Changsha, China.
authors: Zhengxiang
authors: Z
authors: Zhou
authors: Department of Histology and Embryology, Xiangya School of Medicine, Central South University, 172 Tongzipo Road, Changsha, China.
authors: Jinxing
authors: J
authors: Cai
authors: Cardiovascular Division, Xiangya Hospital, Central South University, Changsha, China.
authors: Ke
authors: K
authors: Xia
authors: Department of pharmacy, The School of Pharmaceutical Sciences, Central South University, 172 Tongzipo Road, Changsha, China.
authors: Qubo
authors: Q
authors: Zhu
authors: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, United States.
authors: Jun
authors: J
authors: Qi
authors: Department of Histology and Embryology, Xiangya School of Medicine, Central South University, 172 Tongzipo Road, Changsha, China.
authors: He
authors: H
authors: Huang
authors: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States. Electronic address: jplutzky@rics.bwh.harvard.edu.
authors: Jorge
authors: J
authors: Plutzky
authors: Cardiovascular Division, Xiangya Hospital, Central South University, Changsha, China. Electronic address: tianluny@163.com.
authors: Tianlun
authors: T
authors: Yang
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D012319:RNA Polymerase II / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D035683:MicroRNAs; D016328:NF-kappa B; D009687:Nuclear Proteins; D012319:RNA Polymerase II; D012333:RNA, Messenger; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C542542:MIRN146 microRNA, human; C524942:MIRN155 microRNA, human
keywords: BET bromodomain; Inflammation; NF-κB; Super enhancer; microRNA