期刊
IMMUNITY
卷 47, 期 2, 页码 235-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2017.07.017
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类别
资金
- N.I.H.
- Tow Foundation
Mechanisms by which interferon (IFN)-gamma activates genes to promote macrophage activation are well studied, but little is known about mechanisms and functions of IFN-gamma-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-gamma-primed human macrophages. IFN-gamma suppressed basal expression of genes corresponding to an M2''-like homeostatic and reparative phenotype. IFN-gamma repressed genes by suppressing the function of enhancers enriched for binding by transcription factor MAF. Mechanistically, IFN-gamma disassembled a subset of enhancers by inducing coordinate suppression of binding by MAF, lineagedetermining 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-gamma-mediated repression. These results identify enhancer inactivation and disassembly as a mechanism of IFN-gamma-mediated gene repression and reveal that MAF regulates the macrophage enhancer landscape and is suppressed by IFN-gamma to augment macrophage activation.
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