IRF5:RelA interaction targets inflammatory genes in macrophages.
IRF5:RelA interaction targets inflammatory genes in macrophages.
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DOI：
10.1016/j.celrep.2014.07.034
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发表时间：
2014-09-11
期刊：
影响因子：
8.8
通讯作者：
Udalova IA
中科院分区：
文献类型：
--
作者：
Saliba DG;Heger A;Eames HL;Oikonomopoulos S;Teixeira A;Blazek K;Androulidaki A;Wong D;Goh FG;Weiss M;Byrne A;Pasparakis M;Ragoussis J;Udalova IA
干扰素调节因子5（IRF 5）在建立炎性巨噬细胞表型中起主要作用，但其转录活性的分子基础尚未完全了解。在这项研究中，我们进行了一个全面的基因组分析IRF 5招募巨噬细胞刺激细菌脂多糖，并发现IRF 5结合到高度转录基因的调控元件。蛋白质：DNA微阵列分析表明，IRF 5在体外识别典型的IRF结合（干扰素刺激反应元件[ISRE]）基序。然而，IRF 5在体内的结合似乎依赖于其与其他蛋白质的相互作用。IRF 5与非经典复合PU.1：ISRE基序结合，其募集由RelA辅助。在IRF 5和RelA缺陷的巨噬细胞中的全局基因表达分析突出了RelA：IRF 5顺式组在调节关键炎性基因的子集中的直接作用。我们绘制了RelA：IRF 5相互作用结构域，并建议干扰它将提供选择性靶向巨噬细胞炎症活动。分析IRF 5在LPS刺激的巨噬细胞中的全基因组功能。IRF 5顺式组与RelA顺式组在多个位点重叠。显示IRF 5和RelA在LPS刺激的巨噬细胞中的全基因组结合在多个位点重叠。IRF 5和RelA靶向高度诱导性炎症基因的调控元件。IRF 5被募集到复合PU. 1：ISRE基序，并且其结合由NF-κB辅助。这项研究系统地定义了IRF 5和RelA转录调控炎症基因的关键子集的机制，并强调IRF 5：RelA相互作用界面作为特定干预措施的靶点。
Interferon Regulatory Factor 5 (IRF5) plays a major role in setting up an inflammatory macrophage phenotype, but the molecular basis of its transcriptional activity is not fully understood. In this study, we conduct a comprehensive genome-wide analysis of IRF5 recruitment in macrophages stimulated with bacterial lipopolysaccharide and discover that IRF5 binds to regulatory elements of highly transcribed genes. Analysis of protein:DNA microarrays demonstrates that IRF5 recognizes the canonical IRF-binding (interferon-stimulated response element [ISRE]) motif in vitro. However, IRF5 binding in vivo appears to rely on its interactions with other proteins. IRF5 binds to a noncanonical composite PU.1:ISRE motif, and its recruitment is aided by RelA. Global gene expression analysis in macrophages deficient in IRF5 and RelA highlights the direct role of the RelA:IRF5 cistrome in regulation of a subset of key inflammatory genes. We map the RelA:IRF5 interaction domain and suggest that interfering with it would offer selective targeting of macrophage inflammatory activities. Genome-wide function of IRF5 in LPS-stimulated macrophages was analyzed IRF5 cistrome overlaps with RelA cistrome at multiple loci IRF5 targets regulatory elements of highly inducible inflammatory genes IRF5 recruitment to key inflammatory loci is assisted by RelA Saliba et al. show that the genome-wide binding of IRF5 and RelA in LPS-stimulated macrophages overlaps at multiple loci. IRF5 and RelA target regulatory elements of highly inducible inflammatory genes. IRF5 is recruited to a composite PU.1:ISRE motif, and its binding is aided by NF-κb. This study systematically defines the mechanism of IRF5 and RelA transcriptional regulation of a key subset of inflammatory genes and highlights IRF5:RelA interaction interface as a target for specific interventions.
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DOI：
10.1126/science.1162327
发表时间：
2009-06-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badis G;Berger MF;Philippakis AA;Talukder S;Gehrke AR;Jaeger SA;Chan ET;Metzler G;Vedenko A;Chen X;Kuznetsov H;Wang CF;Coburn D;Newburger DE;Morris Q;Hughes TR;Bulyk ML
通讯作者：
Bulyk ML
影响因子：
2.8
作者：
Eames, H. L.;Saliba, D. G.;Udalova, I. A.
通讯作者：
Udalova, I. A.
影响因子：
7
作者：
Gordan, Raluca;Hartemink, Alexander J.;Bulyk, Martha L.
通讯作者：
Bulyk, Martha L.
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
20.3
作者：
Krausgruber, Thomas;Saliba, David;Udalova, Irina A.
通讯作者：
Udalova, Irina A.