Transcriptional Pause Release Is a Rate-Limiting Step for Somatic Cell Reprogramming
Transcriptional Pause Release Is a Rate-Limiting Step for Somatic Cell Reprogramming
复制标题
转录暂停释放是体细胞重编程的限速步骤。
DOI：
10.1016/j.stem.2014.09.018
复制
发表时间：
2014-11-06
期刊：
影响因子：
23.9
通讯作者：
Esteban, Miguel A.
中科院分区：
文献类型：
--
作者：
Liu, Longqi;Xu, Yan;Esteban, Miguel A.
在体细胞重编程期间通过外源转录因子的多能性网络的再活化涉及染色质重塑和RNA聚合酶II（Pol II）向靶位点的募集。在这里，我们报告说，Pol II是从事多能性启动子在重编程，但仍然暂停和无效释放。我们还表明，含溴结构域蛋白4（BRD 4）刺激生产性转录延伸的多能性基因的解离暂停释放因子P-TEFb从一个无活性的复合物含有HEXIM 1。因此，BRD 4过表达增强了重编程效率，HEXIM 1抑制了重编程效率，而Brd 4和Hexim 1敲低则相反。我们进一步证明重编程因子KLF 4有助于将P-TEFb招募到多能性启动子。因此，我们的工作提供了一种机制来解释多能性基因在重编程中的重新激活，并揭示了KLF 4在转录暂停释放中的意想不到的作用。
Reactivation of the pluripotency network during somatic cell reprogramming by exogenous transcription factors involves chromatin remodeling and the recruitment of RNA polymerase II (Pol II) to target loci. Here, we report that Pol II is engaged at pluripotency promoters in reprogramming but remains paused and inefficiently released. We also show that bromodomain-containing protein 4 (BRD4) stimulates productive transcriptional elongation of pluripotency genes by dissociating the pause release factor P-TEFb from an inactive complex containing HEXIM1. Consequently, BRD4 overexpression enhances reprogramming efficiency and HEXIM1 suppresses it, whereas Brd4 and Hexim1 knockdown do the opposite. We further demonstrate that the reprogramming factor KLF4 helps recruit P-TEFb to pluripotency promoters. Our work thus provides a mechanism for explaining the reactivation of pluripotency genes in reprogramming and unveils an unanticipated role for KLF4 in transcriptional pause release.