ENL initiates multivalent phase separation of the super elongation complex (SEC) in controlling rapid transcriptional activation
ENL initiates multivalent phase separation of the super elongation complex (SEC) in controlling rapid transcriptional activation
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ENL 启动超延伸复合物 (SEC) 的多价相分离来控制快速转录激活
DOI：
10.1126/sciadv.aay4858
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发表时间：
2020-04-01
期刊：
影响因子：
13.6
通讯作者：
Lin, Chengqi
中科院分区：
文献类型：
--
作者：
Guo, Chenghao;Che, Zhuanzhuan;Lin, Chengqi
SEC可以通过LLPS将P-TEFb与无活性的可溶性HEXIM 1复合物区室化，以调节快速转录事件。暂停的RNA聚合酶II（Pol II）的释放需要将正转录延伸因子B（P-TEF B）掺入超延伸复合物（SEC）中，从而导致快速但同步的转录激活。然而，P-TEFb从非活性状态到活性状态的动态转变的机制仍然不清楚。在此，我们发现SEC组分能够通过液-液相分离从含有P-TEFb复合物的可溶性无活性HEXIM 1中区室化和浓缩P-TEFb。具体地，ENL或其固有无序区域足以引发SEC的液滴形成。AFF 4与ENL一起在流化SEC液滴中起作用。SEC液滴在血清暴露后快速且动态地形成，并且是快速转录诱导所需的。我们还发现ENL与MLL的融合可以促进SEC相分离。总之，我们的研究结果表明SEC的多价相分离在控制转录暂停释放中起着关键作用。
SEC can compartmentalize P-TEFb via LLPS from the inactive soluble HEXIM1 complex to regulate rapid transcriptional events. Release of paused RNA polymerase II (Pol II) requires incorporation of the positive transcription elongation factor b (P-TEFb) into the super elongation complex (SEC), thus resulting in rapid yet synchronous transcriptional activation. However, the mechanism underlying dynamic transition of P-TEFb from inactive to active state remains unclear. Here, we found that the SEC components are able to compartmentalize and concentrate P-TEFb via liquid-liquid phase separation from the soluble inactive HEXIM1 containing the P-TEFb complex. Specifically, ENL or its intrinsically disordered region is sufficient to initiate the liquid droplet formation of SEC. AFF4 functions together with ENL in fluidizing SEC droplets. SEC droplets are fast and dynamically formed upon serum exposure and required for rapid transcriptional induction. We also found that the fusion of ENL with MLL can boost SEC phase separation. In summary, our results suggest a critical role of multivalent phase separation of SEC in controlling transcriptional pause release.