DNMT1相关的DNA被动去甲基化在体细胞重编程中的选择性

项目名称： DNMT1相关的DNA被动去甲基化在体细胞重编程中的选择性

项目编号： No.91519305

项目类型： 重大研究计划

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 郑辉

作者单位： 中国科学院广州生物医药与健康研究院

项目金额： 75万元

中文摘要： 促进细胞增殖和降低DNMT1表达可以有效降低细胞整体DNA甲基化水平并提高体细胞重编程效率。前期研究表明，DNA甲基化的稳定遗传需要DNMT1在G1期继续发挥功能，而缩短G1期长度可以影响DNMT1发挥作用并导致DNMT1被动去甲基化。对TET1与DNMT1在重编程中相互作用以及神经细胞转分化系统的研究提示DNA甲基化遗传尤其是相关的被动去甲基化可能具有选择性。因此，本项目计划利用高通量基因组甲基化测序，首先确定DNA甲基化遗传在细胞增殖的不同时期具有怎样的选择性，然后阐明促进细胞增殖和降低DNMT1表达导致的DNA被动去甲基化在正常成纤维细胞中以及重编程过程中的选择性，最后结合转录组测序确定DNA被动去甲基化对体细胞重编程的调控机制。研究结果也可以为研究DNA主动（TET）和被动去甲基化在重编程中的关系以及神经细胞转分化机制提供新的思路，并进一步研究细胞命运转换的表观遗传学机制服务。

中文关键词： DNA甲基化遗传；DNA被动去甲基化；DNMT1；重编程；细胞周期

英文摘要： Both increasing cell proliferation and decreasing DNMT1 expression reduce the global DNA methylation level and promote reprogramming significantly. During our preliminary studies, DNA methylation inheritance requires the function of DNMT1 during G1 phase, shorten G1 phase with cell cycle-related regulators impairs the function of DNMT1 and leads to passive DNA demethylation. Additional studies on the interactions between TET1 and DNMT1 during reprogramming and on the trans-differentiation system from fibroblast to neurons suggest the DNA inheritance and passive DNA demethylation might have selectivity during different cell cycle phases. Thus the current project plans to use whole genome DNA methylation sequencing to investigate, 1) the selectivity of DNA inheritance during different cell cycle phases; 2) the selectivity of passive DNA demethylation during proliferation acceleration or DNMT1 down-regulation in untreated MEFs or in MEFs subjected for reprogramming; 3) combine the whole genome DNA methylation pattern with RNA-seq analysis and explore the contribution of passive DNA demethylation to reprogramming. The current results may also facilitate the understanding on the interactions between DNA active demethylation by TET1 and passive demethylation by DNMT1 during reprogramming and the mechanisms underlying

英文关键词： DNA methylation inheritance;；DNA Passive Demethylation；DNMT1；Reprogramming；Cell Cycle