Integrator mediates the biogenesis of enhancer RNAs.
Integrator mediates the biogenesis of enhancer RNAs.
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DOI：
10.1038/nature14906
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发表时间：
2015-09-17
期刊：
影响因子：
64.8
通讯作者：
Shiekhattar R
中科院分区：
文献类型：
--
作者：
Lai F;Gardini A;Zhang A;Shiekhattar R
整合子是与RNA聚合酶II（RNAPII）的C-末端结构域（CTD）稳定缔合的多亚基复合物。整合子具有核心的催化RNA内切酶活性，这是非多聚腺苷酸化的RNAPII依赖的富含尿苷酸的小核RNA基因（UsnRNA）的3′-末端加工所必需的。在这里，我们研究了来自远端调控元件（增强子）参与组织和时间特异性调控基因表达的转录物的生物发生中的整合子的要求。整合子以刺激依赖性方式被募集到增强子和超级增强子。整合子亚基的功能缺失减少了eRNA的信号依赖性诱导，并消除了刺激诱导的增强子-启动子染色质环。全局核运行和RNAPII分析揭示了Integrator在eRNA初级转录物的3′端切割中的作用，导致转录终止。在不存在整合子的情况下，eRNA保持与RNAPII结合，并且它们的初级转录物积累。重要的是，eRNA的诱导和基因表达反应需要整合子复合物的催化活性。我们提出了一个作用的整合子在生物合成的eRNA和增强子功能的后生动物。
Integrator is a multi-subunit complex stably associated with the C-terminal domain (CTD) of RNA polymerase II (RNAPII) . Integrator is endowed with a core catalytic RNA endonuclease activity, which is required for the 3′-end processing of non-polyadenylated RNAPII-dependent uridylate-rich small nuclear RNA genes (UsnRNAs) . Here, we examined the requirement of Integrator in the biogenesis of transcripts derived from distal regulatory elements (enhancers) involved in tissue- and temporal-specific regulation of gene expression . Integrator is recruited to enhancers and super-enhancers in a stimulus-dependent manner. Functional depletion of Integrator subunits diminishes the signal-dependent induction of eRNAs and abrogates the stimulus-induced enhancer-promoter chromatin looping. Global nuclear run-on and RNAPII profiling reveals a role for Integrator in 3′-end cleavage of eRNAs primary transcripts leading to transcriptional termination. In the absence of Integrator, eRNAs remain bound to RNAPII and their primary transcripts accumulates. Importantly, the induction of eRNAs and gene expression responsiveness requires the catalytic activity of Integrator complex. We propose a role for Integrator in biogenesis of eRNAs and enhancer function in metazoans.