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Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription

机译：Rev-Erbs通过抑制增强子定向转录来抑制巨噬细胞基因表达

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摘要

Rev-Erb-a and Rev-Erb-P are nuclear receptors that regulate the expression of genes involved in the control of circadian rhythm, metabolism and inflammatory responses. Rev-Erbs function as transcriptional repressors by recruiting nuclear receptor co-repressor (NCoR)-HDAC3 complexes to Rev-Erb response elements in enhancers and promoters of target genes, but the molecular basis for cell-specific programs of repression is not known. Here we present evidence that in mouse macrophages Rev-Erbs regulate target gene expression by inhibiting the functions of distal enhancers that are selected by macrophage-lineage-determining factors, thereby establishing a macrophage-specific program of repression. Remarkably, the repressive functions of Rev-Erbs are associated with their ability to inhibit the transcription of enhancer-derived RNAs (eRNAs). Furthermore, targeted degradation of eRNAs at two enhancers subject to negative regulation by Rev-Erbs resulted in reduced expression of nearby messenger RNAs, suggesting a direct role of these eRNAs in enhancer function. By precisely defining eRNA start sites using a modified form of global run-on sequencing that quantifies nascent 5' ends, we show that transfer of full enhancer activity to a target promoter requires both the sequences mediating transcription-factor binding and the specific sequences encoding the eRNA transcript. These studies provide evidence for a direct role of eRNAs in contributing to enhancer functions and suggest that Rev-Erbs act to suppress gene expression at a distance by repressing eRNA transcription.%双向非编码RNA是从增强子元素转录来的，但不清楚这些“来自增强子的RNAs”(eRNAs)是有功能性作用还是仅仅只是增强子活性的一种反映。本期Nature上两篇文章从不同核受体的正负转录功能的角度研究了这一问题。Wenbo Li等人提供了eRNA转录在乳腺癌细胞系中的雌激素受体激发基因过程中具有功能上的重要性的证据；Michael Lam等人发现，巨噬细胞中的Rev-Erb核受体的抑制功能与它们能够抑制eRNAs转录的能力有关。这两项研究综合起来，为eRNAs在为增强子功能做贡献中起一定作用提供了证据。
机译：Rev-Erb-a和Rev-Erb-P是核受体，可调节参与昼夜节律，代谢和炎症反应控制的基因的表达。 Rev-Erbs通过将核受体共阻遏物（NCoR）-HDAC3复合体募集到目标基因的增强子和启动子中的Rev-Erb反应元件中而起转录阻遏物的作用，但是细胞特异性阻遏程序的分子基础尚不明确。在这里我们提供的证据表明，在小鼠巨噬细胞中，Rev-Erbs通过抑制由巨噬细胞谱系决定因子选择的远端增强子的功能来调节靶基因表达，从而建立了巨噬细胞特异性的阻遏程序。值得注意的是，Rev-Erbs的抑制功能与其抑制增强子来源的RNA（eRNA）转录的能力有关。此外，在受Rev-Erbs负调节作用的两个增强子处靶向降解eRNA，导致附近信使RNA的表达减少，表明这些eRNA在增强子功能中的直接作用。通过使用修饰形式的全球自动测序来精确定义eRNA起始位点，该测序定量了新生的5'末端，我们证明了将完整增强子活性转移至目标启动子既需要介导转录因子结合的序列，又需要编码该序列的特定序列。 eRNA转录本。这些研究为eRNA在促进增强子功能中的直接作用提供了证据，并表明Rev-Erbs通过抑制eRNA转录在一定距离上抑制基因表达。％双重非编码RNA是从增强子元素转录来的，但不清楚这些“来自增强子的RNA”（eRNA）是有功能性作用还是只是只是增强子活性的一种反映。本期自然上两篇文章从不同核受体的正负转录功能的角度研究了这一个问题。WenboLi等人提供了eRNA转录在糖尿病细胞系中的雌激素受体激发基因过程中具有功能上的明显的证据； Michael Lam等人发现，巨噬细胞中的Rev-Erb核这方面研究综合起来，为eRNAs在为增强子功能做贡献中起一定作用提供了证据。

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  • 来源
    《Nature》 |2013年第7455期|511-515395397|共7页
  • 作者

    Michael T. Y. Lam; Han Cho; Hanna P. Lesch; David Gosselin; Sven Heinz; Yumiko Tanaka-Oishi; Christopher Benner; Minna U. Kaikkonen; Aneeza S. Kim; Mika Kosaka; Cindy Y. Lee; Andy Watt; Tamar R. Grossman; Michael G. Rosenfeld; Ronald M. Evans; Christopher K. Glass;

  • 作者单位

    Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.;

    Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.;

    Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.;

    Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.;

    Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.;

    Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.;

    Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.;

    Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.;

    lsis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, California 92010, USA.;

    Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.;

    Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.;

    lsis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, California 92010, USA.;

    lsis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, California 92010, USA.;

    Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA, Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815-6789, USA;

    Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA, Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815-6789, USA;

    Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.;

  • 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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