The transcription factor STAT6 mediates direct repression of inflammatory enhancers and limits activation of alternatively polarized macrophages

Research output: Contribution to journalArticle

  • External authors:
  • Zsolt Czimmerer
  • Bence Daniel
  • Attila Horvath
  • Gergely Nagy
  • Mate Kiss
  • Matthew Peloquin
  • Marietta M Budai
  • Ixchelt Cuaranta-Monroy
  • Laszlo Steiner
  • Bela Nagy Jr
  • Szilard Poliska
  • Csaba Banko
  • Zsolt Bacso
  • Ira G Schulman
  • Sascha Sauer
  • Jean François Deleuze
  • Szilvia Benko
  • László Nagy

Abstract

The molecular basis of signal-dependent transcriptional activation has been
extensively studied in macrophage polarization, however our understanding remains limited regarding the molecular determinants of repression. Here we show that IL-4- activated STAT6 transcription factor is required for the direct transcriptional repression of a large number of genes during in vitro and in vivo alternative macrophage polarization. Repression results in decreased lineage-determining transcription factor, p300 and RNA polymerase II binding followed by reduced enhancer RNA expression, H3K27 acetylation and chromatin accessibility. The repressor function of STAT6 is HDAC3-dependent on a subset of IL-4-repressed genes. In addition, STAT6-repressed enhancers show extensive overlap with the NF-κB p65 cistrome and exhibit decreased esponsiveness to lipopolysaccharide after IL-4 stimulus on a subset of genes. As a consequence, macrophages exhibit diminished inflammasome activation, decreased IL-1β production and pyroptosis. Thus, IL-4-STAT6 signaling pathway establishes an alternative polarization-specific epigenenomic signature resulting in dampened macrophage responsiveness to inflammatory stimuli.

Bibliographical metadata

Original languageEnglish
JournalImmunity
DOIs
StatePublished - 16 Jan 2018