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Shape of promoter antisense RNAs regulates ligand-induced transcription activation

机译：启动子反义RNA的形状调节配体诱导的转录激活

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摘要

The size of the transcriptional program of long non-coding RNAs in the mammalian genome has engendered discussions about their biological roles~(1), particularly the promoter antisense (PAS) transcripts~(2,3). Here we report the development of an assay-referred to as chromatin isolation by RNA-Cas13a complex-to quantitatively detect the distribution of RNA in the genome. The assay revealed that PAS RNAs serve as a key gatekeeper of a broad transcriptional pause release program, based on decommissioning the 7SK small nuclear RNA-dependent inhibitory P-TEFb complex. Induction of PAS RNAs by liganded ERα led to a significant loss of H3K9me3 and the release of basally recruited HP1α and KAP1 on activated target gene promoters. This release was due to PAS RNA-dependent recruitment of H3K9me3 demethylases, which required interactions with a compact stem-loop structure in the PAS RNAs, an apparent feature of similarly regulated PAS RNAs. Activation of the ERα-bound MegaTrans enhancer, which is essential for robust pause release, required the recruitment of phosphorylated KAP1, with its transfer to the cognate promoters permitting 17β-oestradiol-induced pause release and activation of the target gene. This study reveals a mechanism, based on RNA structure, that mediates the function of PAS RNAs in gene regulation.
机译：在哺乳动物基因组中长期非编码RNA的转录程序的大小对其生物学作用〜（1），特别是启动子反义（PAS）转录物〜（2,3）。在这里，我们通过RNA-CAS13A复合物报告了作为染色质分离的测定分离的测定 - 以定量检测基因组中RNA的分布。该测定揭示了PAS RNA作为广泛转录暂停释放程序的关键网守，基于退役7SK小核RNA依赖性抑制p-TEFB复合物。通过配体ERα诱导PAS RNA导致H3K9ME3的显着损失，并在激活的靶基因启动子上释放基本募集的HP1α和KAP1。该释放是由于H3K9ME3去甲基酶的PAS RNA依赖性募集，其在PAS RNA中与紧凑的茎环结构相互作用，这是类似调节的PAS RNA的表观特征。激活Erα-结合的巨盐载体增强剂，这对于鲁棒暂停释放至关重要，所以需要募集磷酸化的KAP1，其转移到允许17β-雌二醇诱导的暂停释放和靶基因的激活来转移到同源促进剂。本研究揭示了基于RNA结构的机制，该机制介导PAS RNA在基因调节中的功能。

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  • 来源
    《Nature》 |2021年第7867期|444-449|共6页
  • 作者

    Fan Yang; Bogdan Tanasa; Rudi Micheletti; Kenneth A Ohgi; Aneel K Aggarwal; Michael G Rosenfeld;

  • 作者单位

    Howard Hughes Medical Institute Department and School of Medicine University of California;

    Department of Ophthalmology Stanford University School of Medicine;

    Howard Hughes Medical Institute Department and School of Medicine University of California;

    Howard Hughes Medical Institute Department and School of Medicine University of California;

    Department of Pharmacological Sciences Icahn School of Medicine at Mount Sinai;

    Howard Hughes Medical Institute Department and School of Medicine University of California;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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