本申请项目针对指南中“生物大分子化学修饰在生理过程和病理变化中的调控机制”研究重点展开。m6A修饰是近年来热点研究的一种在RNA上的动态可逆化学修饰，由催化亚基METTL3-METTL14和调控亚基WTAP蛋白组成的m6A甲基转移酶复合物催化，可以影响生物体内多种重要功能。m6A甲基转移酶复合物的功能异常会引起一系列包括癌症、发育和代谢迟缓及神经系统紊乱在内的多种人类疾病。虽然近年来针对甲基转移酶复合物的研究取得了长足的进展，但仍有很多重要的基本科学问题亟需解决。本申请课题将综合采用生物化学、结构生物学、化学生物学和细胞生物学等多学科方法来研究和阐明m6A甲基转移酶复合物的组装机制和调控机理，对WTAP蛋白自身多聚性质进行结构和功能研究，并解析WTAP蛋白介导的多个调控复合物的结构和调控机制。相关研究将为深入理解m6A甲基转移酶复合物组装提供分子基础，有助于后续潜在药物开发和疾病治疗研究。

This research proposal aims at the key research direction of “the regulation mechanisms of chemical modification of biological macromolecules in physiological processes and pathological changes”. N6-methyladenosine (m6A) modification is a dynamic and reversible chemical modification on RNAs, playing crucial roles in mRNA dynamics and thus affecting nearly every aspect of physiological functions. m6A modification is catalyzed by the core complex of RNA methyltransferase (writers), including the catalytic subunit METTL3-METTL14 protein complex and the regulatory subunit WTAP protein. The dysfunction of m6A methyltransferase leads to severe human diseases including cancers, delay in development and metabolism and neuronal disorders and so on. The recent explosion of interests in m6A modification and the writer complex has prompted tremendous progresses in this field. However, there are still many important fundamental questions related to m6A modification and the methyltransferase complex needed to be addressed. In this research proposal, we combine multidisciplinary approaches including biochemistry, structure biology, chemical biology and cell biology methods to elucidate the molecular mechanism underlying the assembly and regulation of m6A methyltransferase complex, to uncover the structure and function of the oligomer state of WTAP protein, and to solve the complex structures of multiple WTAP-mediated regulatory protein complexes. The research will provide a molecular basis for an in-depth understanding of the assembly of the m6A methyltransferase complex, which will facilitate subsequent potential drug development and medical treatments of relevant disease research.