title: IFN-γ Induces Histone 3 Lysine 27 Trimethylation in a Small Subset of Promoters to Stably Silence Gene Expression in Human Macrophages.
abstract: The mechanisms by which IFN-γ activates expression of interferon-stimulated genes that have inflammatory and host defense functions are well understood. In contrast, little is known about how IFN-γ represses gene expression. By using transcriptomic and epigenomic analysis, we found that stable repression of a small group of genes by IFN-γ is associated with recruitment of the histone methyltransferase EZH2 and deposition of the negative mark histone 3 lysine 27 trimethylation (H3K27me3) at their promoters. Repressed genes included MERTK, PPARG, and RANK, which have anti-inflammatory functions and promote osteoclast differentiation. Gene repression and H3K27me3 persisted after IFN-γ signaling was terminated, and these silenced genes were no longer responsive to glucocorticoids, IL-4, and M-CSF. These results identify cytokine-induced H3K27 trimethylation as a mechanism that stabilizes gene silencing in macrophages. IFN-γ-induced macrophage activation is thus reinforced by a chromatin-based mechanism that blocks anti-inflammatory and opposing pathways.
authors.affiliation: Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Kyuho
authors.initials: K
authors.lastname: Kang
authors.affiliation: Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA; Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn, NY 11201, USA.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Giannopoulou
authors.affiliation: Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Celeste
authors.initials: C
authors.lastname: Fang
authors.affiliation: Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA; Department of Medicine, Weill Cornell Medical College and Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA. Electronic address: ivashkivl@hss.edu.
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
mesh_terms: D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism; D020868:Gene Silencing / Q000502:physiology*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D008239:Lysine; D008262:Macrophage Activation / Q000235:genetics* / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D006657:Histones; D007371:Interferon-gamma; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D008239:Lysine