Nucleic Acids Res首次揭示调控转录延伸暂停重启的分子机制

　　

       陈瑞川教授课题组在《Nucleic Acids Research》在线发表了“Multiple P-TEFbs cooperatively regulate the release of promoter-proximally paused RNA polymerase II”的研究论文。

         近年来，得益于全基因组高通量测序的技术广泛应用于真核基因转录调控的研究，人们逐渐形成共识：后生动物的基因转录存在两种调控模式，即转录起始调控模式和转录延伸暂停与重启调控模式。采用转录延伸暂停与重启模式来调控的基因，通常与细胞应激、细胞增殖与分化等相关，其内在的调控机制并不清楚。

       陈瑞川课题组通过高通量质谱以及ChIP-seq等技术研究发现，细胞内存在多种活化的P-TEFb激酶复合体，通过磷酸化不同延伸抑制因子，以解除其对转录延伸的抑制作用，从而调控转录延伸暂停的重启、并刺激全长mRNA的合成。研究进一步发现：这些不同P-TEFb复合体，以类似信号传递的方式，通过不同的募集通道被募集到不同的延伸抑制因子上，从而形成复杂的网络调控机制，对处于转录延伸暂停状态的基因进行延伸重启调控。

        该研究首次详细阐述了调控转录延伸暂停重启的分子机制；部分修正和完善了过去十几年由我们及其他实验室所建立的基因转录延伸由单一P-TEFb调控的理论。同时，该研究为深入理解生命体，在特定信号和环境刺激下的基因转录调控模式的研究提供了重要的理论基础。

        该论文的共同第一作者为2011级博士陆小冬、2012级博士朱鑫星、2013级博士李游以及我院教师刘敏。

原文摘要：

Multiple P-TEFbs cooperatively regulate the release of promoter-proximally paused RNA polymerase II

The association of DSIF and NELF with initiated RNA Polymerase II (Pol II) is the general mechanism for inducing promoter-proximal pausing of Pol II. However, it remains largely unclear how the paused Pol II is released in response to stimulation. Here, we show that the release of the paused Pol II is cooperatively regulated by multiple P-TEFbs which are recruited by bromodomain-containing protein Brd4 and super elongation complex (SEC) via different recruitment mechanisms. Upon stimulation, Brd4 recruits P-TEFb to Spt5/DSIF via a recruitment pathway consisting of Med1, Med23 and Tat-SF1, whereas SEC recruits P-TEFb to NELF-A and NELF-E via Paf1c and Med26, respectively. P-TEFb-mediated phosphorylation of Spt5, NELF-A and NELF-E results in the dissociation of NELF from Pol II, thereby transiting transcription from pausing to elongation. Additionally, we demonstrate that P-TEFb-mediated Ser2 phosphorylation of Pol II is dispensable for pause release. Therefore, our studies reveal a co-regulatory mechanism of Brd4 and SEC in modulating the transcriptional pause release by recruiting multiple P-TEFbs via a Mediator- and Paf1c-coordinated recruitment network.