School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China.
Southeast University-Allen Institute Joint Center, Institute for Brain and Intelligence, Southeast University, Nanjing, 210096, China.
Sci Adv. 2020 Apr 1;6(14):eaay4858. doi: 10.1126/sciadv.aay4858. eCollection 2020 Apr.
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.
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-TEFb）掺入超级延伸复合物（SEC）中，从而导致快速而同步的转录激活。然而，P-TEFb 从无活性状态到活性状态的动态转变的机制仍不清楚。在这里，我们发现 SEC 成分能够通过液-液相分离将 P-TEFb 从包含 P-TEFb 复合物的可溶性无活性 HEXIM1 中分隔和浓缩。具体来说，ENL 或其固有无序区域足以启动 SEC 的液滴形成。AFF4 与 ENL 一起在 SEC 液滴的流体化中起作用。SEC 液滴在血清暴露时快速且动态形成，是快速转录诱导所必需的。我们还发现，ENL 与 MLL 的融合可以促进 SEC 的相分离。总之，我们的结果表明 SEC 的多价相分离在控制转录暂停释放中起着关键作用。
