A BRD4-mediated elongation control point primes transcribing RNA polymerase II for 3′-processing and termination
A BRD4-mediated elongation control point primes transcribing RNA polymerase II for 3′-processing and termination
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DOI：
10.1016/j.molcel.2021.06.026
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发表时间：
2021-09-02
期刊：
影响因子：
16
通讯作者：
Mayer, Andreas
中科院分区：
文献类型：
--
作者：
Arnold, Mirjam;Bressin, Annkatrin;Mayer, Andreas
转录延伸已成为后生动物基因表达的调节中心。主要控制点发生在 RNA 聚合酶 II (Pol II) 释放进入生产性延伸之前的早期延伸期间。先前的研究已将 BRD4 与转录延伸联系起来。在这里，我们使用快速 BET 蛋白和 BRD4 选择性降解以及定量全基因组方法来研究 BRD4 在 Pol II 转录调控中的直接功能。值得注意的是，作为急性 BRD4 丢失的直接后果，启动子近端暂停释放受损，并且转录参与的 Pol II 经过此检查点进行转录通读。综合蛋白质组范围分析揭示了延伸和 3'-RNA 加工因子作为核心 BRD4 相互作用因子。 BRD4 消融破坏了 5'-控制区一般 3'-RNA 加工因子的募集，这与 RNA 裂解和终止缺陷相关。这些在人类细胞中进行的研究揭示了 BRD4 介导的检查点，并开始在 5'-延伸控制和 3'-RNA 加工之间建立分子联系。
Transcription elongation has emerged as a regulatory hub in gene expression of metazoans. A major control point occurs during early elongation before RNA polymerase II (Pol II) is released into productive elongation. Prior research has linked BRD4 with transcription elongation. Here, we use rapid BET protein and BRD4-selective degradation along with quantitative genome-wide approaches to investigate direct functions of BRD4 in Pol II transcription regulation. Notably, as an immediate consequence of acute BRD4 loss, promoter -proximal pause release is impaired, and transcriptionally engaged Pol II past this checkpoint undergoes read through transcription. An integrated proteome-wide analysis uncovers elongation and 3'-RNA processing factors as core BRD4 interactors. BRD4 ablation disrupts the recruitment of general 3'-RNA processing factors at the 5'-control region, which correlates with RNA cleavage and termination defects. These studies, performed in human cells, reveal a BRD4-mediated checkpoint and begin to establish a molecular link between 5'-elongation control and 3'-RNA processing.