Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages

Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):E2865-74. doi: 10.1073/pnas.1121131109. Epub 2012 Jul 16.

Abstract

Histone deacetylases (HDACs) regulate inflammatory gene expression, as indicated by the potent antiinflammatory activity of pan-HDAC inhibitors. However, the specific contribution of each of the 11 HDAC proteins to the inflammatory gene expression program is unknown. Using an integrated genomic approach, we found that Hdac3-deficient macrophages were unable to activate almost half of the inflammatory gene expression program when stimulated with LPS. A large part of the activation defect was attributable to loss of basal and LPS-inducible expression of IFN-β, which maintains Stat1 protein levels in unstimulated cells and acts in an autocrine/paracrine manner after stimulation to promote a secondary wave of Stat1-dependent gene expression. Loss of Hdac3-mediated repression of nuclear receptors led to hyperacetylation of thousands of genomic sites and associated gene derepression. The up-regulation of the constitutively expressed prostaglandin endoperoxide synthase, Ptgs1 (Cox-1), a nuclear receptor target, had a causative role in the phenotype because its chemical inhibition reverted, albeit partially, the Ifn-β activation defect. These data indicate a central role for Hdac3 in inflammation and may have relevance for the use of selective Hdac inhibitors as antiinflammatory agents.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Chromatin Immunoprecipitation
  • Cyclooxygenase 1 / metabolism
  • Cytokines / analysis
  • DNA Primers / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Gene Expression Regulation / genetics*
  • Genomics
  • Histone Deacetylases / deficiency
  • Histone Deacetylases / metabolism*
  • Macrophages / metabolism*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, DNA

Substances

  • Cytokines
  • DNA Primers
  • Membrane Proteins
  • Cyclooxygenase 1
  • Ptgs1 protein, mouse
  • Histone Deacetylases
  • histone deacetylase 3

Associated data

  • GEO/GSE33162
  • GEO/GSE33163
  • GEO/GSE33164