Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Nat Struct Mol Biol. 2013 Feb;20(2):182-7. doi: 10.1038/nsmb.2476. Epub 2013 Jan 6.
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.
组蛋白去乙酰化酶 3（HDAC3）是一种表观遗传修饰酶，对于正常的小鼠发育和组织特异性功能是必需的。在体外，HDAC3 蛋白本身的酶活性极小，但通过与核受体辅阻遏物 NCOR1 和 SMRT 中包含的保守去乙酰化酶激活结构域（DAD）的稳定结合获得其组蛋白去乙酰化功能。在这里，我们表明，尽管具有正常水平的 HDAC3 蛋白，但在同时携带 NCOR1 和 SMRT 的 DAD 点突变（NS-DADm）的小鼠中，HDAC3 酶活性无法检测到。局部组蛋白乙酰化增加，基因组 HDAC3 募集减少但未被消除。值得注意的是，NS-DADm 小鼠可以出生并存活至成年，而 HDAC3 的遗传缺失则是胚胎致死的。这些发现表明，核受体辅阻遏物在体内对于 HDAC3 酶活性是必需的，并表明 HDAC3 的一种去乙酰化酶非依赖性功能可能对于生命是必需的。
