IFN-γ Induces Histone 3 Lysine 27 Trimethylation in a Small Subset of Promoters to Stably Silence Gene Expression in Human Macrophages

Cell Rep. 2016 Sep 20;16(12):3121-3129. doi: 10.1016/j.celrep.2016.08.051.

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.

MeSH terms

  • DNA Methylation
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Gene Silencing / physiology*
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Interferon-gamma / biosynthesis*
  • Interferon-gamma / genetics
  • Lysine
  • Macrophage Activation / genetics*
  • Macrophage Activation / immunology
  • Macrophages / immunology*
  • Promoter Regions, Genetic / genetics

Substances

  • Histones
  • Interferon-gamma
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Lysine