Polη调控氢醌所致肝细胞DNA损伤反应的表观遗传学机制研究

环境遗传毒性因素常常会引起DNA损伤。为了维持基因组完整性，细胞通过进化形成了一套称为DNA损伤反应（DDR）的机制来处理DNA损伤。我们在前期研究中发现，跨损伤合成酶Polη在氢醌诱导肝细胞DDR过程中起着重要的作用，但Polη调控DDR的表观遗传学机制尚未阐明。本研究拟建立氢醌诱导肝细胞DDR实验模型，通过检测DNA甲基转移酶、组蛋白乙酰转移酶及去乙酰化酶的活性、DNA损伤反应性miRNAs表达水平、DNA甲基转移酶、甲基化结合蛋白、组蛋白乙酰化酶和去乙酰化酶以及DDR蛋白的表达特征，结合基因组DNA整体甲基化、DDR基因启动子区甲基化及其转录调控区域组蛋白修饰状况，探讨氢醌诱导DDR条件下肝细胞内Polη与DNA甲基化、组蛋白修饰及miRNA之间的关系，阐明Polη在氢醌诱导肝细胞DDR过程中的表观遗传调控作用及其可能机制，从而为建立机体对氢醌所致损伤的防御体系提供科学的理论依据。

Lesions in DNA are frequently caused by environmental and genotoxic agents. To maintain the integrity of genome, cells have evolved mechanisms termed the "DNA damage response (DDR)" to deal with DNA lesions. Our previous studies suggest that translesion syntesis DNA polymerase eta (Polη) play important roles in DDR induced by hydroquinone. However, the epigenetic mechanism of DDR mediated by Polη has not yet been elucidated. In this study, experimental model of DDR induced by hydroquinone in hepatocytes will be established. By detecting the activities of DNA methyltransferases, histone acetyltransferases and histone deacetylases, the expression levels of DNA damage inducible miRNAs, and the epression characteristics of DNA methyltransferases, methylation binding proteins, histone acetyltransferases, histone deacetylases and DDR proteins, and combined with status of genome DNA methylation, methylation in promoter regions and histone modifications in transcription regulatory regions of DDR genes, the relationship between DNA methylation, histone modifications, miRNA and Polη will be explored and the epigenetic regulation mechanism of Polη to DDR induced by hydroquinone in hepatocytes will be clarified, which will provide scientific theoretical basis to establish the body defense system to the damage caused by hydroquinone.