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

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.