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

TY - JOUR

T1 - Nuclear receptor co-repressors are required for the histone-deacetylase activity of HDAC3 in vivo

AU - You, Seo-Hee

AU - Lim, Hee-Woong

AU - Sun, Zheng

AU - Broache, Molly

AU - Won, Kyoung-Jae

AU - Lazar, Mitchell A

PY - 2013/2

Y1 - 2013/2

N2 - 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.

AB - 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.

KW - Animals

KW - Blotting, Western

KW - Chromatin Immunoprecipitation

KW - Crosses, Genetic

KW - Histone Deacetylases/genetics

KW - Immunoprecipitation

KW - Male

KW - Mice

KW - Mice, Mutant Strains

KW - Nuclear Receptor Co-Repressor 1/genetics

KW - Nuclear Receptor Co-Repressor 2/genetics

KW - Point Mutation/genetics

KW - Protein Array Analysis

KW - Protein Structure, Tertiary/genetics

U2 - 10.1038/nsmb.2476

DO - 10.1038/nsmb.2476

M3 - Journal article

C2 - 23292142

SN - 1545-9993

VL - 20

SP - 182

EP - 187

JO - Nature Structural & Molecular Biology

JF - Nature Structural & Molecular Biology

IS - 2

ER -