BET蛋白介导的超级增强子形成是microRNA表达调控的新机制

Numerous studies show that microRNAs extensively regulate genes transcription through mediating target mRNAs degradation. However, very few researches focused on the regulation of microRNAs themselves. And the genome-wide epigenetic regulation of microRNA coding genes transcription are largely unknown..Through collaborating with Harvard Medical School, we published our recent work in Molecular Cell, which demonstrated that super-enhancers co-formed by BET proteins and NF-kB regulate protein coding genes transcription. Suppression of BET proteins selectively down-regulated proinflammatory genes transcription and attenuated atherosclerosis. Given this groundbreaking finding, we further did microRNA sequence and found that BET proteins are involved in the regulation of HUVEC microRNA coding genes transcription as well. .Accordingly, our previous findings prompt us to demonstrate the following two hypotheses by utilizing the novel chemicals (JQ1, biotin-JQ1) and epigenetic technologies. #1. Whether super-enhancers formed by BET proteins regulate microRNA coding genes transcription genome-wide? #2. Whether the expression of microRNAs driven by super-enhancers are critical in the development of inflammation and adipogenesis. The demonstration of the hypotheses will offer new insights and avenues for microRNA epigenetic regulation study.

大量研究表明microRNA通过介导目的mRNA降解广泛参与了基因转录后调控。但目前对microRNA本身转录调控研究还较少，尤其是在全基因组范围的microRNA表观遗传调控还鲜有报道。.最近本课题组与哈佛医学院合作在Molecular Cell杂志首次报道BET蛋白与NF-kB共同形成的超级增强子是蛋白编码基因转录调控的关键机制，而抑制BET蛋白选择性打破了“促炎超级增强子”并改善了动脉粥样硬化。此外已完成的预实验也证实BET蛋白参与了microRNA编码基因转录调控。.基于上述发现我们将利用最新开发的一些化学分子，运用Chem-seq等表观遗传技术论证如下科学假说：BET蛋白介导形成的超级增强子在全基因组范围参与了microRNA编码基因转录调控，这些microRNA进而在炎症、成脂等生理及病理过程中发挥关键作用。本课题的开展将为microRNA表观遗传调控奠定新的理论基础。

microRNA通过介导目的mRNA降解广泛参与了基因转录后调控，但立项时科学界对microRNA本身转录调控研究还较少，尤其是在全基因组范围的microRNA表观遗传调控还鲜有报道。 本课题组与哈佛医学院合作在Molecular Cell杂志首次报道BET蛋白与NF-kB共同形成的超级增强子是蛋白编码基因转录调控的关键机制，而抑制BET蛋白选择性打破了“促炎超级增强子”并改善了动脉粥样硬化。在此基础上我们研究了BET蛋白对microRNA转录调控的机制。.在这项研究中，我们利用ChIP+二代测序的方法分析了microRNA启动子和增强子区BRD4蛋白、RNA POL II的富集情况，证实炎症诱导了BRD4介导的“超级增强子”形成，从而调控了microRNA的表达，而上调的microRNA又反过来调控了炎症相关的蛋白编码基因，从而避免了过度炎症反应，将炎症控制在机体可控水平。体内体外实验均证实BRD4介导的“超级增强子”上调microRNA146a和micro155，下调炎症基因表达，使炎症处于可控范围。.在这一项目及其后续项目的资助下本课题组开拓性的发现了BET蛋白对microRNA的表观遗传调控机制，并且发表了一系列研究结果，这些研究成果较为系统的阐明了机体如何在分子水平维持炎症基因转录调控的平衡，从而保证机体对炎症的适度反应。这一发现提示了机体在分子水平实现的一种自我保护机制。探索研究发现，BET蛋白在成脂及血液系统疾病中也有着重要作用。