Interferon-γ Represses M2 Gene Expression in Human Macrophages by Disassembling Enhancers Bound by the Transcription Factor MAF.
Interferon-γ Represses M2 Gene Expression in Human Macrophages by Disassembling Enhancers Bound by the Transcription Factor MAF.
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干扰素-γ通过拆卸由转录因子MAF绑定的增强剂来抑制人类巨噬细胞中的M2基因表达。
DOI：
10.1016/j.immuni.2017.07.017
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发表时间：
2017-08-15
期刊：
影响因子：
32.4
通讯作者：
Ivashkiv LB
中科院分区：
文献类型：
--
作者：
Kang K;Park SH;Chen J;Qiao Y;Giannopoulou E;Berg K;Hanidu A;Li J;Nabozny G;Kang K;Park-Min KH;Ivashkiv LB
干扰素(IFN)-γ激活基因促进巨噬细胞活化的机制研究得很好，但对IFN-γ介导的基因抑制的机制和功能知之甚少。我们使用综合转录组学和表观基因组学方法分析了IFN-γ引发的人巨噬细胞的染色质可及性、组蛋白修饰、转录因子结合和基因表达。IFN-γ抑制了与‘ M2 ’样稳态和修复表型相对应的基因的基础表达。IFN-γ通过抑制转录因子MAF富集的增强子的功能来抑制基因。从机制上讲，IFN-γ通过诱导MAF、决定谱系的转录因子和染色质可及性对结合的协同抑制来分解一组增强子。从类风湿性关节炎患者分离的巨噬细胞中，与maf结合增强子相关的基因被抑制，揭示了IFN-γ介导的抑制的疾病相关特征。这些结果确定了增强子失活和分解是IFN-γ介导的基因抑制的一种机制，并揭示了MAF作为巨噬细胞增强子的调节因子，被IFN-γ抑制以增强巨噬细胞的激活。
Mechanisms by which interferon (IFN)-γ activates genes to promote macrophage activation are well studied, but little is known about mechanisms and functions of IFN-γ-mediated gene repression. We used an integrated transcriptomic and epigenomic approach to analyze chromatin accessibility, histone modifications, transcription factor binding, and gene expression in IFN-γ-primed human macrophages. IFN-γ suppressed basal expression of genes corresponding to an ‘M2’-like homeostatic and reparative phenotype. IFN-γ repressed genes by suppressing the function of enhancers enriched for binding by transcription factor MAF. Mechanistically, IFN-γ disassembled a subset of enhancers by inducing coordinate suppression of binding by MAF, lineage-determining transcription factors, and chromatin accessibility. Genes associated with MAF-binding enhancers were suppressed in macrophages isolated from rheumatoid arthritis patients, revealing a disease-associated signature of IFN-γ–mediated repression. These results identify enhancer inactivation and disassembly as a mechanism of IFN-γ-mediated gene repression, and reveal MAF as a regulator of the macrophage enhancer landscape that is suppressed by IFN-γ to augment macrophage activation.
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影响因子：
16
作者：
Calo, Eliezer;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
DOI：
10.1038/nrm3949
发表时间：
2015-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
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作者：
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通讯作者：
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30.5
作者：
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通讯作者：
Ivashkiv, LB
影响因子：
64.5
作者：
Gosselin D;Link VM;Romanoski CE;Fonseca GJ;Eichenfield DZ;Spann NJ;Stender JD;Chun HB;Garner H;Geissmann F;Glass CK
通讯作者：
Glass CK