Deacetylase-independent function of HDAC3 in transcription and metabolism requires nuclear receptor corepressor

Mol Cell. 2013 Dec 26;52(6):769-82. doi: 10.1016/j.molcel.2013.10.022. Epub 2013 Nov 21.

Abstract

Histone deacetylases (HDACs) are believed to regulate gene transcription by catalyzing deacetylation reactions. HDAC3 depletion in mouse liver upregulates lipogenic genes and results in severe hepatosteatosis. Here we show that pharmacologic HDAC inhibition in primary hepatocytes causes histone hyperacetylation but does not upregulate expression of HDAC3 target genes. Meanwhile, deacetylase-dead HDAC3 mutants can rescue hepatosteatosis and repress lipogenic genes expression in HDAC3-depleted mouse liver, demonstrating that histone acetylation is insufficient to activate gene transcription. Mutations abolishing interactions with the nuclear receptor corepressor (NCOR or SMRT) render HDAC3 nonfunctional in vivo. Additionally, liver-specific knockout of NCOR, but not SMRT, causes metabolic and transcriptomal alterations resembling those of mice without hepatic HDAC3, demonstrating that interaction with NCOR is essential for deacetylase-independent function of HDAC3. These findings highlight nonenzymatic roles of a major HDAC in transcriptional regulation in vivo and warrant reconsideration of the mechanism of action of HDAC inhibitors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Animals
  • Fatty Liver / enzymology
  • Fatty Liver / genetics
  • Gene Expression Profiling / methods
  • Genotype
  • HEK293 Cells
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology*
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / deficiency
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Histones / metabolism*
  • Humans
  • Lipid Metabolism* / drug effects
  • Lipid Metabolism* / genetics
  • Liver / drug effects
  • Liver / enzymology*
  • Male
  • Mice
  • Mice, Knockout
  • Models, Molecular
  • Mutation
  • Nuclear Receptor Co-Repressor 1 / genetics
  • Nuclear Receptor Co-Repressor 1 / metabolism*
  • Nuclear Receptor Co-Repressor 2 / genetics
  • Nuclear Receptor Co-Repressor 2 / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Protein Conformation
  • Structure-Activity Relationship
  • Transcription, Genetic* / drug effects
  • Transfection

Substances

  • Histone Deacetylase Inhibitors
  • Histones
  • Ncor1 protein, mouse
  • Ncor2 protein, mouse
  • Nuclear Receptor Co-Repressor 1
  • Nuclear Receptor Co-Repressor 2
  • Histone Deacetylases
  • histone deacetylase 3

Associated data

  • GEO/GSE49365
  • GEO/GSE49386
  • GEO/GSE49387
  • GEO/GSE51045