增强子甲基化修饰异常在食管鳞癌发生发展中的机制研究

Esophageal squamous cell carcinoma (ESCC) is a common and aggressive malignancy, with particularly high morbidity and mortality in China. Recently, large-scale genomic profiling has revealed many important and frequent genomic aberrations in ESCC, advancing our understanding of its pathogenesis. However, the epigenetic abnormalities in ESCC have not yet been identified, and the associated biological significance is unclear..Our recent studies have uncovered distinct methylation alterations in numerous enhancer regions in ESCC, and we found that the methylation level of enhancers correlates negatively with the expression of the associated genes. Through whole-genome bisulfite sequencing (WGBS), chromatin immunoprecipitaion sequencing (ChIP-seq), and RNA sequencing (RNA-seq) analyses, we have identified a number of novel ESCC-driven genes with enhancer methylation alterations, such as ZNF36L2, etc. In this proposal, we will comprehensively characterize methylation changes in enhancer regions in ESCC via integrative epigenome approaches, and determine transcriptional deregulation and identify novel driver genes. Our work aims at further unveiling the epigenetic abnormalities in ESCC, establishing an important molecular foundation for understanding the pathogenesis of ESCC. This work will also have the potential to promote the development of early diagnosis and targeted therapy for this deadly malignancy.

食管鳞癌是常见的消化道恶性肿瘤，其发病率和死亡率在我国一直居高不下。近几年基因组测序工作揭示了许多重要、高频的食管鳞癌基因组畸变，对于阐明其发病机理具有重要意义。然而，与基因组畸变互补的另一重要层面的生物学过程：“表观遗传调控”在食管鳞癌中的异常改变和分子机制至今未明。.我们近期的研究揭示食管鳞癌中大量增强子区域存在甲基化改变，并发现增强子甲基化程度与下游基因的表达呈现负相关。结合全基因组亚硫酸盐测序（WGBS）、免疫沉淀结合高通量测序（ChIP-seq）和全转录组测序（RNA-seq）分析，我们鉴定出一批新的食管鳞癌增强子甲基化改变的相关癌基因（如ZNF36L2）。本项目，我们将在食管鳞癌组织中全面鉴定甲基化异常改变的增强子片段，筛选并验证与此类表观遗传调控异常相关的肿瘤驱动基因。这些工作将全面揭示食管鳞癌中的表观遗传调控异常，更好地阐明食管鳞癌发生发展的分子机制，为其诊疗提供新思路。

通过本项目研究，我们系统地鉴定出了44个潜在的鳞癌特异性核心转录因子，并首次从DNA甲基化、组蛋白修饰和转录调控三个方面初步揭示了核心转录因子DLX5在鳞癌中异常激活的分子机制。在组蛋白修饰方面，我们首次发现DLX5基因启动子在肿瘤发生中呈现双向染色质重塑现象，并从远端增强子的角度阐明了SOX2驱动DLX5启动子组蛋白激活的机制。同时我们还发现高表达DLX5与TP63相互作用调控2000个增强子和启动子，进而促进鳞状细胞癌的恶性增殖。我们的结果初步揭示了鳞癌发生中的转录调控网络，阐明了一种在癌症发展过程中促进染色质重塑的表观遗传新机制。