小分子调控DNA甲基化的结构与功能研究

项目名称： 小分子调控DNA甲基化的结构与功能研究

项目编号： No.91419301

项目类型： 重大研究计划

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 徐彦辉

作者单位： 复旦大学

项目金额： 200万元

中文摘要： DNA甲基化是重要的表观遗传修饰。TET蛋白氧化DNA甲基化并参与DNA去甲基化过程，在胚胎发育，表观遗传调控的细胞编程与重编程过程中起作用。申请人前期工作解析了TET2-DNA复合物晶体结构，揭示了TET蛋白识别和催化DNA甲基化的分子机制(2013,Cell，唯一通讯作者)。以往研究及申请人前期工作发现多种小分子，如维他命C，ATP和α-KG类似物等，能够显著影响TET蛋白酶活性，调控DNA甲基化的动态变化。某些代谢小分子在肿瘤中大量累积，引起DNA甲基化紊乱导致肿瘤。本项目拟解析TET蛋白与多种小分子复合物的晶体结构，通过结构与功能研究，阐明小分子激活或抑制TET蛋白酶活性的分子机制，项目的完成将深入揭示小分子通过TET蛋白酶活性，参与DNA甲基化动态调节的分子机制，并为设计和开发靶向TET蛋白的药物奠定重要的结构生物学基础。

中文关键词： TET蛋白；DNA甲基化修饰；表观遗传调控；结构生物学；小分子

英文摘要： DNA methylation is an important epigenetic modification. TET proteins oxidize methylation of DNA and play important roles in regulation of embryo development, cellular programming and re-programming. The applicant previously report crystal structure of TET2 in complex with 5mC-modified DNA, which reveals the molecular mechanisms of substrate recognition and catalysis by TET2 (Cell, 2013). Previous studies and data from our groups indicate that small molecules, such as ATP, Vitamin C and α-KG analogues, could active or inhibit TET dioxygenases activity. Particularly，some metabolites heavily accumulated in tumors，which are tightly associated with tumorgenesis through regulating epigenetic modification enzymes. The exploration of this phenomenon will have profound significance in understanding the mechanism of TET-mediated regulation of DNA methylation by small molecules。 We here proposed to determine the crystal structure of TET in complex with these small molecules. The studies will reveal mechanisms by which small molecules regulate DNA methylation through modulating enzymatic activity of TET proteins. The accomplishment of this project will also lay a solid structural foundation for discovering agonists or antagonists of TET proteins.

英文关键词： TET protein；DNA methylation；epigenetic regulation；structural biology；small molecule