组蛋白修饰酶SETD2功能缺失促进MLL白血病发生的表观遗传调控机制

项目名称： 组蛋白修饰酶SETD2功能缺失促进MLL白血病发生的表观遗传调控机制

项目编号： No.81500142

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 陈艾莉

作者单位： 中国科学院北京基因组研究所

项目金额： 18万元

中文摘要： 组蛋白修饰在白血病发生中占有重要地位且为潜在治疗靶点，然而目前对组蛋白修饰紊乱的致病机制研究尚不明确。我们前期研究发现组蛋白修饰酶SETD2在急性白血病中频繁突变，引起组蛋白H3第36位赖氨酸三甲基化（H3K36me3）修饰的紊乱，是一个关键的抑癌基因。本项目以SETD2突变最常见的白血病亚型（MLL白血病）为模型，探讨组蛋白甲基化修饰在肿瘤驱动作用中的分子机制。我们将整合RNA-Seq和ChIP-Seq等功能基因组手段研究H3K36甲基化修饰的基因组定位及其对白血病转录紊乱的调控作用，探索MLL基因易位导致的组蛋白甲基化紊乱（H3K79）和SETD2介导的表观通路（H3K36）在白血病发生的协同作用机制，最后通过功能实验验证关键基因和信号通路的作用。研究将在分子水平揭示SETD2突变引发白血病的致病机理，对阐明表观遗传机制促进肿瘤发生有重要科学意义，为开发新的治疗策略提供潜在的关键靶点。

中文关键词： SETD2；MLL白血病；H3K36甲基化；H3K79甲基化；组蛋白修饰

英文摘要： Histone modifications play important roles in leukemogenesis and are potential therapeutic targets, however the pathogenic mechanism of histone modification disorders is not clear. Our previous study showed that histone methyltransferase SETD2 is frequently mutated in acute leukemia, notably with the highest mutation frequency (22%) in MLL-rearranged leukemia, which causes dysregulation of histone H3 lysine 36 tri-methylation (H3K36me3). Therefore, the study provides compelling evidence for SETD2 as a new tumor suppressor gene. In this project, we will use MLL-rearranged leukemia as a disease model to study the molecular mechanism of histone methylation in driving tumorigenesis. Functional genomics tools such as RNA-seq and ChIP-seq will be used to study the whole-genome localization and transcription regulation of H3K36 methylation. We will also investigate the cooperation between H3K79 and H3K36 methylation dysregulations during leukemia development, which are caused by MLL translocation and SETD2 mutation, respectively. Eventually, the biology function of critical genes and signaling pathways will be validated by in vivo and in vitro experiments. This study will reveal the pathogenic mechanism of SETD2 mutation in leukemia on the molecular level, is of important scientific significance in elucidating the epigenetic mechanisms to promote tumorigenesis, and can provide potential key targets for developing new therapeutic strategy.

英文关键词： SETD2;MLL leukemia;H3K36 methylation;H3K79 methylation;Histone modification