转录中介体在体细胞重编程中的表观遗传学调控作用

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 account for cell reprogramming though specific epigenetic modification.

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。

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。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，精细调控特异基因的时空表达，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单泛素水平下降，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，我们发现MED23能够“重编程”癌症细胞生长。首先我们观察到MED23与H2Bub在肺癌病人样本中有较高的水平；结合基因表达谱与ChIP-seq的数据，我们又发现MED23与H2Bub共同控制的基因中与癌症发生发展高度相关。这些观察揭示了体细胞重编程为癌症细胞的一种分子机理。这项研究作为EMBO J封面文章发表，并获同期专评。另外基金执行期间还发表Nature Commun文章，发现中介体对骨发育关键转录因子RUNX2的控制作用。