Nuclear receptor co-repressors are required for the histone-deacetylase activity of HDAC3 in vivo

Nat Struct Mol Biol. 2013 Feb;20(2):182-7. doi: 10.1038/nsmb.2476. Epub 2013 Jan 6.

Abstract

Histone deacetylase 3 (HDAC3) is an epigenome-modifying enzyme that is required for normal mouse development and tissue-specific functions. In vitro, HDAC3 protein itself has minimal enzyme activity but gains its histone-deacetylation function from stable association with the conserved deacetylase-activating domain (DAD) contained in nuclear receptor co-repressors NCOR1 and SMRT. Here we show that HDAC3 enzyme activity is undetectable in mice bearing point mutations in the DAD of both NCOR1 and SMRT (NS-DADm), despite having normal levels of HDAC3 protein. Local histone acetylation is increased, and genomic HDAC3 recruitment is reduced though not abrogated. Notably, NS-DADm mice are born and live to adulthood, whereas genetic deletion of HDAC3 is embryonic lethal. These findings demonstrate that nuclear receptor co-repressors are required for HDAC3 enzyme activity in vivo and suggest that a deacetylase-independent function of HDAC3 may be required for life.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • Chromatin Immunoprecipitation
  • Crosses, Genetic
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Immunoprecipitation
  • Male
  • Mice
  • Mice, Mutant Strains
  • Nuclear Receptor Co-Repressor 1 / genetics
  • Nuclear Receptor Co-Repressor 1 / metabolism*
  • Nuclear Receptor Co-Repressor 2 / genetics
  • Nuclear Receptor Co-Repressor 2 / metabolism*
  • Point Mutation / genetics
  • Protein Array Analysis
  • Protein Structure, Tertiary / genetics

Substances

  • Nuclear Receptor Co-Repressor 1
  • Nuclear Receptor Co-Repressor 2
  • Histone Deacetylases
  • histone deacetylase 3

Associated data

  • GEO/GSE42541