Enzyme-independent functions of HDAC3 in the adult heart
The cardioprotective effects of histone deacetylase (HDAC) inhibitors (HDIs) are at odds with the deleterious effects of HDAC depletion. Here, we use HDAC3 as a prototype HDAC to address this contradiction. We show that adult-onset cardiac-specific depletion of HDAC3 in mice causes cardiac hypertrophy and contractile dysfunction on a high-fat diet (HFD), excluding developmental disruption as a major reason for the contradiction. Genetically abolishing HDAC3 enzymatic activity without affecting its protein level does not cause cardiac dysfunction on HFD. HDAC3 depletion causes robust downregulation of lipid oxidation/bioenergetic genes and upregulation of antioxidant/anti-apoptotic genes. In contrast, HDAC3 enzyme activity abolishment causes much milder changes in far fewer genes. The abnormal gene expression is cardiomyocyte-autonomous and can be rescued by an enzyme-dead HDAC3 mutant but not by an HDAC3 mutant (?33-70) that lacks interaction with the nuclear-envelope protein lamina-associated polypeptide 2ß (LAP2ß). Tethering LAP2ß to the HDAC3 ?33-70 mutant restored its ability to rescue gene expression. Finally, HDAC3 depletion, not loss of HDAC3 enzymatic activity, exacerbates cardiac contractile functions upon aortic constriction. These results suggest that the cardiac function of HDAC3 in adults is not attributable to its enzyme activity but to its nuclear envelope tethering action, which has implications for understanding the cardioprotective effects of HDIs. Overall design: HDAC3 has enzyme dependent and independent  functions, we compared the effect of  HDAC3 KO and HDAC3 inactive mutant NS-DADm recovery in mouse heart protection. The groups used for RNA seq are WT, HDAC3 KO and NS-DADm(HDAC3 inactive).