p63介导的染色质重塑在氡暴露致肺癌发生中的作用及其分子机制研究

染色质重塑通过改变基因表达谱，在细胞分化、胚胎发育和肿瘤发生中有重要作用。p63是决定上皮细胞命运的先锋转录因子，它通过染色质重塑促进了多种癌种的发生发展。我们前期通过对经α粒子辐射诱导建立的人肺癌细胞模型研究发现，p63在该模型中表达显著上调，同时富集在染色质可及性增加且三维空间接触增加的区域，并且可能通过形成肿瘤特异性拓扑相关结构域激活癌基因MYC，因此我们推测p63作为先锋转录因子介导染色质重塑导致α粒子辐射致肺癌发生，该机制在辐射诱导的肺癌发生中尚无文献报道。为了进一步明确p63是否介导染色质重塑导致氡暴露致肺癌发生并阐明其分子机制，本项目拟以氡暴露诱导的肺癌细胞模型为研究对象，利用ATAC-seq、ChIP-seq和RNA-seq等方法获得肺癌发生的染色质重塑特征，找到p63参与染色质重塑的正负向调控因子并进行实验验证。本项目为研究氡暴露致肺癌发生机制提供了新的技术路线。

Chromatin remodeling plays an important role in cell differentiation, embryonic development and tumorigenesis by changing the gene expression profile. As a pioneer factor that determines the fate of epithelial cells, p63 can promote the development and progression of a variety of cancers through chromatin remodeling. In our previous study, we found that with its significantly up-regulated expression in the models of human lung cancer induced by alpha particles radiation, p63 enriched at gained ATAC-seq peaks in contact-increased locus, and may activate MYC oncogene through the formation of tumor-specific topologically associating domains (TADs). Therefore, we speculate that p63 functions as a pioneer factor and regulate chromatin structure remodeling that leading to radiation-induced lung cancer, which has not been reported in the literature. In order to further clarify whether p63 mediates chromatin remodeling in lung cancer induced by radon exposure and elucidate its molecular mechanisms, this project intends to describe the characteristics of chromatin remodeling of radiation induced-lung cancer by bioinformatic analysis following ATAC-seq、ChIP-seq and RNA-seq on the models, figure out the positive and negative regulatory factors of p63 involved in chromatin remodeling, and carry out the experimental verifications. In a word，this project provides a new approach for studying the mechanisms of tumorigenesis in lung cancer induced by radon exposure.