基于超级增强子驱动的核心调控网络在鼻咽癌中的作用及机制研究

鼻咽癌（Nasopharyngeal Carcinoma, NPC）好发于隐蔽位置，恶性程度高,预后不理想，发病机制尚未充分阐明。我们前期通过对鼻咽癌组织和非肿瘤的鼻咽组织进行针对H3K27ac的ChIP-seq，寻找和筛选H3K27ac结合的超级增强子（SE），进一步结合H3K27ac的Hi-ChIP测序，从三维基因组角度解析SE与调控基因之间的互作，其中发现SOX2、IGF1R基因组DNA附近有SE信号，并与启动子DNA有交互联系。在7例鼻咽癌WGS数据中有5例样本发现SOX2的SE区域携有突变。这些携带突变的SE具有更强地诱导转录活性。我们将深入探讨携有突变的SE形成机制，以及SE驱动癌基因的表观调控机制，深层解析这些癌基因促进鼻咽癌进展的下游调控网络。本研究将通过阐明肿瘤关键驱动基因的表观调控机制，为诠释鼻咽癌发生发展的表观遗传机制和寻找鼻咽癌的靶向治疗新手段提供科学依据。

Nasopharyngeal carcinoma is largely asymptomatic and occurs in a concealed location and it often comes with unfavorable prognosis. The pathogenesis of NPC has not been fully elucidated. Previously, we performed ChIP-seq for H3K27ac on nasopharyngeal carcinoma tissues and non-tumor nasopharyngeal tissues to screen and find H3K27ac-bound super enhancers (SE). Then we performed H3K27ac HiChIP-seq to identify in enhancer-promoter looping with NPC-specific super-enhancers. We found that there are the interactions between the promoters and SE signals near the SOX2, IGF1R genomic region. Interestingly, according to the mutation profiling of our WGS data, 5 out of 7 NPC cases harbored the mutations in the SE region of SOX2. Moreover, these mutation-carrying SEs have stronger transcriptional activities. Thus, in this project, we will explore in depth the formation mechanism of SE with mutations and the epigenetic regulation mechanism of SE-driven oncogenes. We will further investigate the downstream regulatory networks of these oncogenes during the progression of nasopharyngeal carcinoma. Above all, this study will provide scientific approach to interpret the epigenetic mechanisms of NPC development and find new targeted therapies for NPC by clarifying the epigenetic regulation of key driven-oncogenes.