Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription.
Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription.
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作者：
Rev-Erbα和Rev-Erbβ是核受体，调节参与控制昼夜节律、代谢和炎症反应的基因的表达。Rev-Erb通过将NCoR/HDAC 3共阻遏物复合物募集到靶基因的增强子和启动子中的Rev-Erb应答元件来发挥转录阻遏物的功能，但细胞特异性阻遏程序的分子基础尚不清楚。在这里，我们提出的证据表明，在巨噬细胞，Rev-Erbs调节靶基因的表达，通过抑制远端增强子的功能，选择巨噬细胞谱系决定因素，从而建立一个巨噬细胞特异性的程序的镇压。值得注意的是，Rev-Erbs的抑制功能与其抑制增强子衍生RNA（eRNA）转录的能力相关。此外，靶向降解的eRNA在两个增强子受到负调控的Rev-Erbs导致附近的mRNA的表达减少，这意味着这些eRNA在增强子功能的直接作用。通过使用定量新生5′末端（5′-GR 0-Seq）的方法精确定义eRNA起始位点，我们表明将完整增强子活性转移到靶启动子需要介导转录因子结合的序列和编码eRNA转录物的特定序列。这些研究为eRNA在促进增强子功能方面的直接作用提供了证据，并表明Rev-Erbs通过抑制eRNA转录来远距离抑制基因表达。
Rev-Erbα and Rev-Erbβ 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 NCoR/HDAC3 co-repressor 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 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 mRNAs, implying a direct role of these eRNAs in enhancer function. By precisely defining eRNA start sites using a method that quantifies nascent 5′ ends (5′-GRO-Seq), 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 direct roles of eRNAs in contributing to enhancer functions and suggest that Rev-Erbs act to suppress gene expression at a distance by repressing eRNA transcription.
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影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
4.5
作者：
Liu AC;Tran HG;Zhang EE;Priest AA;Welsh DK;Kay SA
通讯作者：
Kay SA
影响因子：
64.5
作者：
Hah N;Danko CG;Core L;Waterfall JJ;Siepel A;Lis JT;Kraus WL
通讯作者：
Kraus WL
影响因子：
6.5
作者：
Raspé, E;Duez, H;Staels, B
通讯作者：
Staels, B
DOI：
10.1093/nass/nrn280
发表时间：
2008-01-01
期刊：
Nucleic acids symposium series (2004)
影响因子：
--
作者：
Seth, Punit P;Siwkowski, Andrew;Swayze, Eric E
通讯作者：
Swayze, Eric E