基于超级增强子识别驱动细胞状态变化的关键因子

超级增强子及其关联基因对维系细胞的状态至关重要。我们前期发表的工作已识别出238个正常和肿瘤细胞的核心超级增强子及关联基因。然而，尚不明确究竟哪些是驱动细胞从正常趋向癌变的关键因子，且缺乏有效的系统识别。这里我们结合前期的食管癌特异性超级增强子预实验、核心转录调控环路模型和插入缺失变异的识别模型，提出在肿瘤发生过程中，如果因变异产生新的转录因子结合位点而导致超级增强子形成可能是细胞癌变的重要驱动力的假设。因此拟在本项目中：（1）寻找变异产生结合新转录因子的位点；（2）验证该位点可能招募其他辅助因子形成新的超级增强子的体内及体外证据；（3）探索这些超级转录因子对下游基因特别是驱动细胞癌变可能的分子机制；（4）最后在系统水平，围绕超级增强子，整合各类组学数据，挖掘驱动细胞状态变化的关键因子。本项目的开展不仅有助于理解肿瘤的发生发展的机制，并且为临床预防、治疗肿瘤提供了新的线索。

Super-enhancer and its associated genes play a critical role in maintaining cell type-specific development and differentiation, as well as in the development of various diseases. We have identified master super-enhancers and their associated genes in 238 normal and tumor samples. However, the potential key factors converting normal cells to cancer cells are largely unknown, and the effective and systematic methods to identify them are still unavailable. Here, based on the preliminary data from our study on super-enhancers specifically in esophageal carcinoma, and the established model of the core transcriptional regulatory circuitry and a pipeline of identification of insertion and deletion variants, we hypothesize that a variant may be a driving factor when it creates a de novo motif, which recruits a transcription factor to bind to itself. The transcription factor subsequently recruits other cofactors, leading to the formation of a super-enhancer. Therefore, in this project, we aim to: (1) identify variants which generate de novo motifs recruiting transcription factors to bind to themselves; (2) verify the evidence in vitro and in vivo that other co-transcription factors potentially recruited to binding regions to generate super-enhancers; (3) explore the molecular mechanism of super-transcription-factors for the downstream super-enhancer-associated genes, especially in the transformation of normal cells to cancer cells; (4) finally, systematically integrate various omics data to screen the key factors driving normal cells to be cancer cells. This project will provide innovative insights into the pathophysiology of the cancers, and offer new prevention and therapeutic approaches.