Deacetylase‐dependent and ‐independent role of HDAC3 in cardiomyopathy

Abstract

Cardiomyopathy is a common disease of cardiac muscle that negatively affects cardiac function. HDAC3 commonly functions as corepressor by removing acetyl moieties from histone tails. However, a deacetylase‐independent role of HDAC3 has also been described. Cardiac deletion of HDAC3 causes reduced cardiac contractility accompanied by lipid accumulation, but the molecular function of HDAC3 in cardiomyopathy remains unknown. We have used powerful genetic tools in Drosophila to investigate the enzymatic and nonenzymatic roles of HDAC3 in cardiomyopathy. Using the Drosophila heart model, we showed that cardiac‐specific HDAC3 knockdown (KD) leads to prolonged systoles and reduced cardiac contractility. Immunohistochemistry revealed structural abnormalities characterized by myofiber disruption in HDAC3 KD hearts. Cardiac‐specific HDAC3 KD showed increased levels of whole‐body triglycerides and increased fibrosis. The introduction of deacetylase‐dead HDAC3 mutant in HDAC3 KD background showed comparable results with wild‐type HDAC3 in aspects of contractility and Pericardin deposition. However, deacetylase‐dead HDAC3 mutants failed to improve triglyceride accumulation. Our data indicate that HDAC3 plays a deacetylase‐independent role in maintaining cardiac contractility and preventing Pericardin deposition as well as a deacetylase‐dependent role to maintain triglyceride homeostasis.

Distinct Roles for COMPASS Core Subunits Set1, Trx, and Trr in the Epigenetic Regulation of Drosophila Heart Development

“…2023, 24, x FOR PEER REVIEW 5 of 18 deposition of Pericardin, a type IV collagen that plays a critical role in maintaining Drosophila cardiac tissue integrity (Figure 3C,E). The overabundance of Pericardin indicates a pathophysiological condition of fibrosis and can be used as an indicator of cardiac injury [29][30][31][32]. Cardiomyocytes were marked by the expression of green fluorescent protein (GFP) driven by a Hand gene regulatory element (Figure 3C).…”

H3K36 Di-Methylation Marks, Mediated by Ash1 in Complex with Caf1-55 and MRG15, Are Required during Drosophila Heart Development

“…Unfortunately, few of the many genes that carry candidate variants for congenital heart disease have been validated in animal models [10,32]. For NSD2, its conditional knockdown in the myocardium of a mouse model for cardiac hypertrophy has demonstrated its role in ventricular remodeling linked to H3K36me2 [33]. For Setd2, its knockdown in mouse cardiac progenitors has disrupted cardiovascular development which was associated with decreased H3K36me3 [34].…”