The Role of Class I Histone Deacetylases in Cardiovascular Development and Disease

Histone acetylation/deacetylation is a dynamic process that coordinates proper gene expression through the opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC inhibitors continue to show promise in a multitude of pathological settings such as cancer and heart disease, however the role of individual HDACs remains largely unexplored. Genetic studies have shown class II HDACs regulate developmental and physiological processes through the interaction with and repression of myocyte enhancer factor 2, MEF2, however the biological functions of class I HDACs have not been determined. To potentially understand the role of individual class I HDACs in development and disease, we generated conditional knockout alleles for HDAC1, HDAC2, and HDAC3. Through global and tissue specific analyses, we hope to identify specific roles of these enzymes in developmental, physiological, and pathological settings. Here I show that HDAC1 and HDAC2 act redundantly in controlling cardiac growth, morphogenesis, and contractility. Mice with cardiac-specific deletion of either HDAC1 or HDAC2 are viable and lack obvious phenotypes, however cardiac-specific deletion of both HDAC1 and HDAC2 results in lethality by two weeks of age. These mice show cardiac arrhythmias, dilated cardiomyopathy, and increased expression of calcium channels and skeletal muscle-specific contractile proteins. HDAC3 is an independent regulator of cardiac development. Global deletion of HDAC3 results in embryonic lethality, whereas cardiac-specific deletion of HDAC3 results in massive cardiac hypertrophy by 3 months of age and lethality by 16 weeks. These mice show metabolic abnormalities including up-regulation of genes involved in fatty acid uptake and oxidation, down-regulation of the glucose utilization pathway, and ligand induced myocardial lipid accumulation. Additionally, these hearts show mitochondrial dysfunction and decreased cardiac efficiency. These studies have identified HDAC3 as a central regulator of myocardial energy metabolism. In addition to cardiac studies, tissue-specific deletions in multiple cell-types have led to the discovery that functional redundancy of HDAC1 and HDAC2 is not restricted to postnatal cardiomyocytes, but extends to early cardiomyocytes, endothelial cells, smooth muscle cells, chondrocytes, and neurons. Deletion of HDAC1 or HDAC2 individually in these cell types does not evoke a phenotype, however deletion of both HDAC1 and HDAC2 results in embryonic lethality or neonatal lethality. Taken together, these studies identify HDAC1 and HDAC2 as redundant regulators of multiple cell types during development. Collectively, these studies have identified distinct and specific roles for HDAC1, HDAC2, and HDAC3 during development and disease. Furthermore, these genetic studies have provided mechanistic insight into the pathways regulated by each enzyme. Additional analyses on these mice will prove instrumental to the development of more specific inhibitors for the treatment of a wide array of pathological conditions.