The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages.
The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages.
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DOI：
10.1101/gad.242685.114
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发表时间：
2014-07-15
影响因子：
10.5
通讯作者：
Nagy L
中科院分区：
文献类型：
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作者：
Daniel B;Nagy G;Hah N;Horvath A;Czimmerer Z;Poliska S;Gyuris T;Keirsse J;Gysemans C;Van Ginderachter JA;Balint BL;Evans RM;Barta E;Nagy L
在这里，Nagy及其同事使用全基因组方法来揭示RXR的活性，RXR是核受体超家族的一个神秘成员。预计RXR信号传导在巨噬细胞中具有重大影响，但其配体活化的生物学后果和基因组基础都是未知的。整合RNA-seq，ChIP-seq，GRO-seq和3C-seq，作者揭示了小鼠骨髓源性巨噬细胞中RXR诱导的转录事件的机制。重要的是，这项研究揭示了一种新的生物活性-血管生成-这是由受体促进的。预计RXR信号传导在巨噬细胞中具有重大影响，但其配体活化的生物学后果和基因组基础都是未知的。进行了全面的全基因组研究，以绘制配体RXR介导的转录变化，活性结合位点和顺式相互作用的背景下，巨噬细胞基因组结构。巨噬细胞RXR顺式组具有5200个基因组结合位点，其不受配体的影响。活性增强子的特征在于PU.1结合、增强子RNA的增加和P300募集。利用这些特征，387个配体RXR结合增强子与226个基因连接，这些基因主要位于CTCF/cohesin限制的功能结构域中。使用染色体构象捕获（3C）和3C结合测序（3C-seq）对这些发现进行了分子验证，我们发现选定的长距离增强子通过稳定或RXR诱导的环与启动子通信，并且一些增强子相互作用，形成染色体间网络。一组血管生成基因，包括Vegfa，具有配体RXR控制的增强子，并为巨噬细胞提供了一种新的诱导程序。
Here, Nagy and colleagues use genome-wide approaches to uncover the activity of RXR, an enigmatic member of the nuclear receptor superfamily. RXR signaling is predicted to have a major impact in macrophages, but neither the biological consequence nor the genomic basis of its ligand activation is known. Integrating RNA-seq, ChIP-seq, GRO-seq, and 3C-seq, the authors unravel the mechanism of RXR-induced transcriptional events in mouse bone marrow-derived macrophages. Importantly, this study uncovers a novel biological activity—angiogenesis—that is promoted by the receptor. RXR signaling is predicted to have a major impact in macrophages, but neither the biological consequence nor the genomic basis of its ligand activation is known. Comprehensive genome-wide studies were carried out to map liganded RXR-mediated transcriptional changes, active binding sites, and cistromic interactions in the context of the macrophage genome architecture. The macrophage RXR cistrome has 5200 genomic binding sites, which are not impacted by ligand. Active enhancers are characterized by PU.1 binding, an increase of enhancer RNA, and P300 recruitment. Using these features, 387 liganded RXR-bound enhancers were linked to 226 genes, which predominantly reside in CTCF/cohesin-limited functional domains. These findings were molecularly validated using chromosome conformation capture (3C) and 3C combined with sequencing (3C-seq), and we show that selected long-range enhancers communicate with promoters via stable or RXR-induced loops and that some of the enhancers interact with each other, forming an interchromosomal network. A set of angiogenic genes, including Vegfa, has liganded RXR-controlled enhancers and provides the macrophage with a novel inducible program.
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影响因子：
64.5
作者：
Bhatt DM;Pandya-Jones A;Tong AJ;Barozzi I;Lissner MM;Natoli G;Black DL;Smale ST
通讯作者：
Smale ST
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：
5.3
作者：
Brazda, Peter;Krieger, Jan;Vamosi, Gyoergy
通讯作者：
Vamosi, Gyoergy
影响因子：
64.8
作者：
Chakravarti, D;LaMorte, VJ;Evans, RM
通讯作者：
Evans, RM
影响因子：
64.8
作者：
通讯作者：
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