YY1转录复合体结合超级增强子调控QKI生成circRNA的分子机制研究

肿瘤细胞中许多关键的致癌基因都是由超级增强子驱动的。超级增强子富集在基因组的变异区，与多种疾病谱系密切相关，因此可作为肿瘤生物标记和治疗靶标，在疾病诊断、预后判断和治疗方面发挥重要作用。本项目前期肝癌全转录组测序结果显示过表达YY1 促进QKI的高表达，并且前期实验验证YY1可结合另一个促癌转录因子p65，并且都与染色质重塑调控转录的组蛋白乙酰转移酶p300互作， p300是结合在转录异常活跃的超级增强子上的组蛋白修饰蛋白。因此我们推测YY1形成的复合体可能是结合QKI的超级增强子区域，极大地促进QKI的转录活性，及下游EMT相关的circRNA的生成。进一步通过筛选针对蛋白复合体互作界面的抑制剂先导化合物，提供了一种新型的针对蛋白互作的抑制剂评价方式。

Many of the key oncogenic genes in cancer cells are driven by super enhancers. Super enhancers enriched in gene mutation regions are closely related to many diseases. Therefore, it can be used as tumor biomarker and therapeutic target, playing an important role in disease diagnosis, prognosis and treatment. In this study, the whole genome sequencing results in hepatocellular carcinoma showed that overexpression of YY1 promotes QKI expression. YY1 combined with another cancer-promoting transcription factor - p65, and p300, which functions as histone acetyltransferase that regulates transcription of genes via chromatin remodeling. P300 is a histone modified protein that combines with super enhancers of abnormal transcriptional activity. Therefore, we speculate that the transcription complex of YY1 may bind a super enhancer region of QKI, which greatly promotes the transcriptional activity of QKI and circRNA downstream formation related to EMT. We further screen inhibitors for protein interaction interface, and provided a new inhibitor leads evaluation method for protein interaction.