Interferon-gamma Represses M2 Gene Expression in Human Macrophages by Disassembling Enhancers Bound by the Transcription Factor MAF

Abstract

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.