title: Nuclear receptor co-repressors are required for the histone-deacetylase activity of HDAC3 in vivo.
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.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Seo-Hee
authors.initials: SH
authors.lastname: You
authors.forename: Hee-Woong
authors.initials: HW
authors.lastname: Lim
authors.forename: Zheng
authors.initials: Z
authors.lastname: Sun
authors.forename: Molly
authors.initials: M
authors.lastname: Broache
authors.forename: Kyoung-Jae
authors.initials: KJ
authors.lastname: Won
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D003433:Crosses, Genetic; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism*; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics; D040081:Protein Array Analysis; D017434:Protein Structure, Tertiary / Q000235:genetics; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D000099186:Histone Deacetylase 3