组蛋白甲基转移酶SET1家族蛋白活性调控的结构基础

项目名称： 组蛋白甲基转移酶SET1家族蛋白活性调控的结构基础

项目编号： No.31470737

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 陈勇

作者单位： 中国科学院上海生命科学研究院

项目金额： 85万元

中文摘要： 组蛋白甲基化在许多生物学过程比如异染色质的形成、X染色体的失活、转录调控中起到了重要的作用,而且组蛋白甲基化的异常能导致多种遗传疾病和癌症的发生发展。因此对组蛋白甲基化相关的蛋白酶的结构和功能研究是目前表观遗传学研究的热点。本项目将致力于研究组蛋白H3第四位的赖氨酸的甲基转移酶-SET1家族蛋白复合物，目前该家族蛋白的活性调节和产物特异性等机制还未得以阐明。我们将综合应用X-射线晶体学和低温冷冻电镜的结构生物学手段对SET1蛋白和其调节蛋白WDR5-Ash2L-RbBP5-DPY30形成的五元复合物做一个系统全面的结构阐析，力图揭示SET-WDR5-Ash2L-RbBP5-DPY30复合物的组装、活性调节、产物生成特异性、核小体识别修饰等各方面的分子机制，为深入了解这些蛋白的体内功能奠定基础，并为一系列遗传疾病或癌症的治疗提供潜在的新靶点。

中文关键词： 组蛋白修饰；表观遗传学；组蛋白甲基化；结构生物学

英文摘要： Histone methylation is a critical chemical modification for epigenetic regulation and plays important roles in multiple cellular events, including transcription regulation, heterochromatin formation, X-chromosome silencing. Abnormal histone methylation has been linked to many human diseases and cancers. Thus structural and functional analyses of protein complexes responsible for histone methylation have gained more attention in recent years. In this project, We will focus on SET1-family histone methyltransferases which have essential roles in the maintenance of the histone H3 Lysine 4 (H3K4) methylation status for gene expression during differentiation and development. The histone methyltransferase activity of SET1-family proteins is regulated by four conserved core subunits, WDR5, Ash2L, RbBP5 and DPY30. However, the underlying mechanism of activity regulation remains elusive. There are six SET1-family proteins in mammals, including SET1A, SET1B, and four Mixed Lineage Leukemia proteins (MLL1,MLL2,MLL3,MLL4). They have different methyltransferase product specificities, and play non-redundant roles in cells. We will systematically study structures of three representative members in SET1-family: SET1B, MLL1 and MLL3. We will use X-ray crystallography and cryo electron microscopy to investigate the structures of SET1-family proteins in complex with regulatory proteins WDR5-Ash2L-RbBP5-DPY30. We will also analyze the structural characterization of SET1-complex recognizing nucleosomes. These structural information will provide valuable insights into molecular mechanisms of assembly, activity regulation, product specificity, nucleosome recognition of SET1-family complexes. These results will also give hints of novel drug design for some human diseases caused by dysfunction of SET1-family methyltransferases.

英文关键词： histone modification;epigenetics;histone methylation;structural biology