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

ABSTRACT: Mechanisms by which interferon (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 and 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 enhancers were suppressed in macrophages isolated from rheumatoid-arthritis patients, revealing a disease-associated signature of IFN-?-mediated repression. These results identify enhancer inactivation and disassembly as a mechanism of IFN-?-mediated gene repression and reveal that MAF regulates the macrophage enhancer landscape and is suppressed by IFN-? to augment macrophage activation.

SUBMITTER: Kang K 

PROVIDER: S-EPMC5568089 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature