Laboratory of RNA Epigenetics, Institute of Molecular Biology (IMB), 55128, Mainz, Germany.
Institute of Neurobiology and Developmental Biology, JGU, 55128, Mainz, Germany.
Nat Commun. 2019 Jan 31;10(1):521. doi: 10.1038/s41467-019-08381-0.
Promoter-proximal pausing of RNA polymerase II (Pol II) is a widespread transcriptional regulatory step across metazoans. Here we find that the nuclear exon junction complex (pre-EJC) is a critical and conserved regulator of this process. Depletion of pre-EJC subunits leads to a global decrease in Pol II pausing and to premature entry into elongation. This effect occurs, at least in part, via non-canonical recruitment of pre-EJC components at promoters. Failure to recruit the pre-EJC at promoters results in increased binding of the positive transcription elongation complex (P-TEFb) and in enhanced Pol II release. Notably, restoring pausing is sufficient to rescue exon skipping and the photoreceptor differentiation defect associated with depletion of pre-EJC components in vivo. We propose that the pre-EJC serves as an early transcriptional checkpoint to prevent premature entry into elongation, ensuring proper recruitment of RNA processing components that are necessary for exon definition.
RNA 聚合酶 II（Pol II）启动子近端暂停是后生动物中广泛存在的转录调控步骤。在这里，我们发现核外显子连接复合物（pre-EJC）是这个过程的关键和保守的调节剂。pre-EJC 亚基的耗竭导致 Pol II 暂停的全面减少，并过早进入延伸。这种效应至少部分是通过 pre-EJC 成分在启动子上的非典型募集来发生的。在启动子上未能募集 pre-EJC 会导致正转录延伸复合物（P-TEFb）的结合增加，并增强 Pol II 的释放。值得注意的是，恢复暂停足以挽救外显子跳跃，并挽救与体内耗尽 pre-EJC 成分相关的光感受器分化缺陷。我们提出，pre-EJC 作为一个早期转录检查点，以防止过早进入延伸，确保适当招募对exon 定义必要的 RNA 加工成分。
