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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 that MAF regulates the macrophage enhancer landscape and is suppressed by IFN-γ to augment macrophage activation.IFN-γ suppresses basal expression of M2-like genes in human macrophagesIFN-γ downregulates MAF and targets MAF-binding enhancers for suppressionA subset of IFN-γ-inactivated enhancers loses TF binding and chromatin accessibilityLow MAF expression correlates with a “negative IFN-γ signature” in RA macrophagesKang et al. demonstrate that IFN-γ represses basal expression of M2-like genes by targeting enhancers. IFN-γ induces loss of enhancer binding by MAF and lineage-determining transcription factors, with concomitant “disassembly” and loss of chromatin accessibility. These results provide new insights into how IFN-γ regulates gene expression and activates macrophages.