Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility

TLDR

HDACs repress gene expression by removing acetyl groups from histone tails, and although class I HDAC1 and HDAC2 are ubiquitously expressed, their specific roles in tissue‑specific gene regulation and organogenesis remain undefined. The study aimed to investigate the in vivo functions of HDAC1 and HDAC2 by generating mice with conditional null alleles of both genes. Conditional null alleles of HDAC1 and HDAC2 were created in mice to assess their roles in cardiac development. Global loss of HDAC1 causes embryonic death by E9.5, whereas HDAC2 loss permits survival to the perinatal period but leads to lethal cardiac defects; cardiac‑specific deletion of either gene alone is benign, but loss of both causes neonatal lethality with arrhythmias, dilated cardiomyopathy, and up‑regulation of skeletal‑muscle contractile proteins and calcium channels, demonstrating partially redundant, cell‑autonomous and non‑cell‑autonomous roles of HDAC1/2 in myocardial growth, morphogenesis, and contractility.

Abstract

Histone deacetylases (HDACs) tighten chromatin structure and repress gene expression through the removal of acetyl groups from histone tails. The class I HDACs, HDAC1 and HDAC2, are expressed ubiquitously, but their potential roles in tissue-specific gene expression and organogenesis have not been defined. To explore the functions of HDAC1 and HDAC2 in vivo, we generated mice with conditional null alleles of both genes. Whereas global deletion of HDAC1 results in death by embryonic day 9.5, mice lacking HDAC2 survive until the perinatal period, when they succumb to a spectrum of cardiac defects, including obliteration of the lumen of the right ventricle, excessive hyperplasia and apoptosis of cardiomyocytes, and bradycardia. Cardiac-specific deletion of either HDAC1 or HDAC2 does not evoke a phenotype, whereas cardiac-specific deletion of both genes results in neonatal lethality, accompanied by cardiac arrhythmias, dilated cardiomyopathy, and up-regulation of genes encoding skeletal muscle-specific contractile proteins and calcium channels. Our results reveal cell-autonomous and non-cell-autonomous functions for HDAC1 and HDAC2 in the control of myocardial growth, morphogenesis, and contractility, which reflect partially redundant roles of these enzymes in tissue-specific transcriptional repression.