转录中介体在体细胞重编程中的表观遗传学调控作用

项目名称： 转录中介体在体细胞重编程中的表观遗传学调控作用

项目编号： No.91519311

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： 王纲

作者单位： 中国科学院上海生命科学研究院

项目金额： 75万元

中文摘要： 细胞命运的改变，包括分化和去分化，常常是由转录因子所主导的。转录中介体各个亚基通过与不同转录因子的特异相互作用，整合环境与发育信号，精细 调控特定基因的时空表达，从而控制细胞命运。申请人及其他人研究发现：中介体能够调节基因转录的起始，延伸，终止，以及RNA加工等一系列过程。最近我们通过规模化筛选发现中介体MED23亚基还参与表观遗传调控，通过招募修饰酶RNF20/40复合物来控制组蛋白H2B的单泛素化，从而激活下游基因的转录。此外，MED23敲除后导致H2B单泛素化水平的下降，促进了骨骼肌的分化。鉴于细胞分化与去分化（重编程）是两个相反的过程，我们又初步发现MED23敲除能够抑制体细胞重编程。本项目拟研究MED23亚基是否通过特定表观遗传修饰来调控细胞重编程，并将阐明相应的分子调控机理。

中文关键词： 转录中介体；体细胞编程；表观遗传学调控；MED23；H2B单泛素化

英文摘要： Cell fate changes, including cellular programming and reprogramming are largely directed by transcription factors. The distinct subunits of Mediator complex specifically interact with different transcription factors, to relay the environmental and developmental signaling for fine-tuning the temporal and spatial gene expression that determine the cell fates. Studies from us and others showed that the Mediator complex plays important roles during transcription initiation, elongation, termination, RNA processing, and possibly epigenetic regulation. We show now that Mediator is indeed an epigenetic regulator. By a screening assay, we identified H2B mono-ubiquitination (H2Bub) as a Mediator MED23-dependent histone modification. And MED23 depletion reduced recruitment of H2Bub modifier RNF20/40 through their interaction in vivo and in vitro. Whole-genome-sequencing analysis revealed that MED23 couples with H2Bub to regulate transcriptional activation. Furthermore, MED23-depletion led to H2Bub deficiency and facilitated myogenesis. Given that differentiation and reprogramming (dedifferentiation) are opposite processes of cell fate determination, and our preliminary works indicated MED23-depletion could inhibit somatic cell reprogramming, we propose here to investigate whether the Mediator MED23 or other subunits may ac

英文关键词： Mediator Complex；Somatic Reprogramming；Epigenetic Regulation；MED23；H2B-ubiquitination