RACK7选择性结合活跃增强子的分子机制及生物学意义的研究

项目名称： RACK7选择性结合活跃增强子的分子机制及生物学意义的研究

项目编号： No.31601060

项目类型： 青年科学基金项目

立项/批准年度： 2017

项目学科： 遗传学与生物信息学、细胞生物学

项目作者： 沈宏杰

作者单位： 复旦大学

项目金额： 16万元

中文摘要： 增强子是一类重要的基因转录调控元件，近年多项研究发现增强子本身也可以发生转录产生enhancer RNA (eRNA)，而eRNA的转录水平与增强子的活性正相关。在已发表的工作中我们已证明RACK7/KDM5C复合物可以定位到活跃增强子区域并通过下调eRNA转录水平抑制其过度活化。本项目拟在MCF-7乳腺癌细胞中深入研究RACK7/KDM5C选择性结合活跃增强子的分子机制并探讨该调控过程对于乳腺癌治疗的意义以寻找新的治疗靶点。前期结果表明，RACK7与eRNA转录的关键调控因子INTS1/12蛋白有较强相互作用；转录抑制剂DRB的处理能显著降低RACK7在增强子上的结合水平；而雌二醇（E2）处理能显著提高依赖E2激活的增强子上RACK7的结合水平。我们就此提出如下假设：增强子上的活跃转录过程能促进RACK7/KDM5C复合物的结合，负反馈抑制eRNA的过度转录，从而抑制增强子的过度活化。

中文关键词： RACK7；特异性结合；增强子；转录；乳腺癌

英文摘要： As important epigenetics regulators, enhancers are recently reported to be actively transcribed to produce enhancer RNA (eRNA), which is positively related to enhancer activity. In our published work we have illustrated that RACK7/KDM5C localize on active enhancers and repress their activity by down-regulating eRNA level. We propose to investigate the mechanism of RACK7/KDM5C’s binding selectivity towards active enhancers. Moreover, by investigating the biological significance of this regulation process in a well-established breast cancer cell line, MCF-7, this study might shed light to new therapies of breast cancer. Our previous study show that RACK7 have strong binding affinity towards INTS1, which is an indispensable factor during eRNA biogenesis. Transcription inhibitors such as DRB strongly repressed the enrichment level of RACK7 on enhancers. On the other hand, Estrogen (E2) treatment greatly promoted RACK7 enrichment level on E2 induced enhancers. Therefore, we bring out the following hypothesis: There is a reverse feedback between RACK7/KDM5C and active transcription on enhancers. As RACK7/KDM5C repressed eRNA transcription, which on the other hand, promote RACK7 binding.

英文关键词： RACK7;Binding selectivity;Enhancer;Transcription;Breast cancer