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

Histone deacetylase 3 (HDAC3) has low enzymatic activity in vitro unless associated with the nuclear receptor corepressors NCOR1 and SMRT through the deacetylase activation domain (DAD). Mice lacking functional DADs in both NCOR1 and SMRT are born and reach adulthood but lack HDAC3 activity, whereas mice lacking HDAC3 are embryonic lethal, which suggests an essential deacetylase-independent function of HDAC3. 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.