MCM2、POLE3调控亲代组蛋白传递的分子机制和生物学功能

表观遗传调控对于细胞身份的建立和维持起着至关重要的作用。表观遗传调控的异常通常导致肿瘤等疾病的发生。组蛋白修饰编码的表观遗传信息被认为是除DNA外，决定细胞命运的另一重要物质。但不清楚组蛋白遗传如何决定子细胞命运。DNA复制是亲代组蛋白遗传的关键步骤，申请人前期开发了能监测组蛋白在复制叉上分配的技术，发现MCM2、POLE3是控制亲代组蛋白传递的关键因子。但，对于MCM2、POLE3参与的调控网络和分子机制，以及如何通过调控组蛋白分配决定子代细胞命运这些问题尚未得到回答。本项目拟利用临近标记的蛋白质组学技术鉴定MCM2、POLE3相互作用蛋白的调控网络。阐明组蛋白传递如何影响子细胞基因表达，以及在干细胞分化、肿瘤异质性产生中的功能。本项目的完成将有助于阐明表观基因组遗传调控和细胞分化命运决定之间的关系，为干细胞的临床治疗应用，肿瘤异质性导致的耐药治疗提供理论依据。

Epigenetic regulation plays a crucial role in the reconstruction and maintenance of cellular identity. The epigenetic regulatory abnormalities often lead to the development of diseases such as tumors. In addition to DNA sequence, the epigenetic information carried by histone modification is another important material that determines the fate of cells. But it is not clear how histone inheritance determines the fate of daughter cells. DNA replication is a key step in parental histone inheritance. In the previous studies, the applicant developed a technique to monitor the segregation of histones on the replication fork, and found that MCM2 and POLE3 are the two key regulators of histone segregation. However, it is not clear the molecular mechanism and the regulatory network of interacting proteins with MCM2 and POLE3, and how the fate of daughter cells is determined by the regulation of histone segregation. Therefore, this project intends to identify the regulatory network of MCM2 and POLE3 by using proximity labeling proteomics technology. Furthermore, we will elucidate how the inheritance of epigenome information encoded by histones affects the gene expression of daughter cells, as well as the functions and molecular mechanisms of the epigenetic regulation in stem cell differentiation and tumor heterogeneity. The completion of this project will bridge the gap between epigenetic inheritance regulation and the fate of cell differentiation, which will provide theoretical basis for the clinical application of stem cells and the drug-resistant treatment of tumor heterogeneity.