IFN-? Represses M2 Gene Expression in Human Macrophages by Suppressing and Disassembling MAF-binding Enhancers [RNA-seq]

Mechanisms by which IFN-? activates genes to promote macrophage activation are well studied, but little is known about mechanisms and functions of IFN-?-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-?-primed human macrophages. IFN-? suppressed basal expression of genes corresponding to an 'M2'-like homeostatic/reparative phenotype. IFN-? repressed genes by suppressing the function of enhancers enriched for binding by transcription factor MAF. Mechanistically, IFN-? '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 disassembled enhancers were suppressed in rheumatoid arthritis macrophages, revealing a disease-associated 'negative IFN-? signature'. These results identify enhancer inactivation and disassembly as a mechanism of IFN-?-mediated gene repression, and MAF as a regulator of the macrophage enhancer landscape that is suppressed by IFN-? to augment macrophage activation. Overall design: RNA-seq in human macrophages stimulated with or without IFN-?, RNA-seq of macrophages transfected with control or MAF-specific siRNA, and RNA-seq of macrophages transduced with control or MAF-expressing adenoviral particles.