长非编码增强子eRNA在CTCF介导的染色质高级拓扑结构调控基因表达中的功能机制研究

哺乳动物基因组中增强子的数量远远大于启动子，并且增强子在组织器官发育中对于基因精准时空表达起到关键作用。近年的研究发现增强子普遍转录长非编码eRNA，其在基因信息传递过程中可能发挥重要作用但具体机制还不清楚。申请人实验室最近发现染色质架构蛋白CTCF与增强子的方向性结合对于原钙粘蛋白增强子与启动子的远程特异性交互作用至关重要，解决了长期悬而未决的增强子方向性问题（Cell，162，900-910. 2015)。我们将详细鉴定原钙粘蛋白增强子和超级增强子eRNA，阐明其在增强子与启动子特异性远程交互作用以及CTCF等染色质架构蛋白调控基因表达的机制。这些研究对于长非编码RNA在基因信息传递过程中的调控作用具有重要意义。

There are far more enhancers than promoters in the mammalian genomes and enhancers are central for precise spatiotemporal gene expression during tissue development and organogenesis. Recent studies have found prevailing transcriptions of long non-coding eRNAs from enhancers that are important for gene regulation but the mechanisms of eRNA functions remain obscure. We recently discovered that the relative orientations and locations of CTCF sites in enhancers and promoters determine the directionality of higher-order chromatin looping and regulation of gene expression. In this grant application, we will characterize the enhancer and super-enhancer eRNAs in the protocadherin gene clusters and dissect their roles in specific long-distance enhancer-promoter looping and in gene regulation through CTCF/cohesin-mediated chromatin topological domains. These studies should have important implications for mechanisms of non-coding RNA function in gene regulation through chromatin architectural proteins such as CTCF.