Twist1转录复合体通过乙酰化修饰调节相分离结合超级增强子促进肝癌恶性演进

细胞内成分能够通过“相分离”的方式相互分开或聚合，相分离异常可能导致多种疾病，如神经退行性疾病、肿瘤等。本项目前期通过pull down-MS及IP等生化实验发现上皮间充质转变的重要转录因子Twist1与组蛋白乙酰转移酶EP300有相互作用。EP300是结合在转录异常活跃的超级增强子上的组蛋白的修饰蛋白。我们进一步检测到Twist1在细胞核中有聚集成核斑点的特征，因此我们猜测Twist1参与的转录复合体的相分离与Twist1乙酰化水平相关。乙酰化的Twist1复合体结合在下游靶基因的超级增强子区域发生相分离，极大地促进基因的转录活性和表达，从而诱发肿瘤恶性演进。我们将尝试寻找打破相分离的先导化合物，并在体内外检测其对肿瘤细胞的抑制作用，这将显示其在抗癌中一致相分离的潜力。

Intracellular components can form some droplets to separate from others or get together with others, this phenomenon is called as "phase separation". Abnormal phase separation may lead to a variety of diseases, such as neurodegenerative diseases, tumors, etc. In the early studies, we found that Twist1, an important transcription factor of epithelial mesenchymal transition (EMT), was found to interact with histone acetyltransferase EP300 by the pull down-MS and IP biochemical experiments. EP300 was known to bind to some super enhancer and can increase the gene transcription activity greatly. Our studies also detected that Twist1 binds EP300 and then can aggregate to form integrated spots like phase separation in the nucleus. We speculated that such phase separation of the large transcription complex may be dependent on the acetylation level of Twist1. The phase separated forms of acetylated Twist1 complex can bind to the super enhancer region of the downstream target genes, greatly promote the transcription activity and the expression of genes, which may induce severe malignancy of tumors. Based on the results, we will try to find the leads to break the phase separation and exam the efficacy of the leads on inhibiting the tumor cells in vitro and in vivo, which will demonstrate potential of inhibiting phase separation in anti-cancer.