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. SOURCE: Lionel,B.,Ivashkiv Hospital for Special Surgery

Pluto Bioinformatics

GSE98368: IFN- Represses M2 Gene Expression in Human Macrophages by Suppressing and Disassembling MAF-binding Enhancers [RNA-seq]