Roles of Class II Histone Deacetylases in the Cardiovascular System

Histone acetylation/deacetylation, which is orchestrated by two opposing families of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs), represents one of the fundamental mechanisms to control gene transcription. Class II histone deacetylases regulate developmental and physiological processes through interaction with and repression of a variety of transcription factors, including myocyte enhancer factor 2 (MEF2). Using gene targeting combined with biochemical assays, the function and regulation of class II HDACs are being elucidated. Here I show that in the absence of HDAC5, the heart becomes profoundly enlarged in response to calcineurin signaling and pressure overload. The cardiac phenotype of HDAC5 mutant mice is remarkably similar to that of HDAC9 mutant mice, strongly suggesting that these two HDACs play comparable roles in the control of cardiac growth. HDAC 5 and 9 also appear to play overlapping roles during heart development, as evidenced by cardiac malformations that occur in mice lacking both genes. Histone deacetylase 7 (HDAC7) is specifically expressed in the endothelium during early embryogenesis. Disruption of the HDAC7 gene in mice results in embryonic lethality due to a failure in endothelial cell-cell adhesion and consequent dilatation and rupture of blood vessels. HDAC7 represses MMP10 gene transcription by associating with MEF2, a direct activator of MMP10 transcription and essential regulator of blood vessel development. By in vitro kinase assays, I showed that class II HDACs are substrates for a novel stressresponsive kinase(s) specific for conserved serines that regulate MEF2-HDAC interactions. A eukaryotic expression screen revealed a remarkable variety of signaling pathways that converge on the signal-responsive phosphorylation sites in HDAC5, thereby enabling HDAC5 to connect extracellular signals to the genome. Microarray analysis was performed to provide a genome-wide molecular description of the target genes of the HDAC5/MEF2 complex in the muscle differentiation pathway. This approach was validated by characterizing the transcriptional regulatory element of a novel gene identified in the microarray analysis, which was confirmed as a direct target of MEF2. Taken together, this study provided mechanistic insights into the regulatory pathways for class II HDACs and the biological functions of these histone modifying enzymes.