Abstract 14180: The Histone Methyltransferase Smyd1 Regulates Cardiac Hypertrophy In Adult Myocardium
Transcriptionally active and inactive chromatin is associated with structurally loosely or densely packed DNA, respectively, a dichotomy correlated with specific post-translational modifications on histones in these regions. While global changes in gene expression are a hallmark of cardiac hypertrophy and failure, much less is known regarding the proteins responsible for modulating histone modifications and chromatin accessibility in the heart. To identify novel chromatin binding proteins active in hypertrophic cardiomyopathy we carried out quantitative proteomic analysis of cardiac chromatin from mice after pressure-overload induced hypertrophy. Among the proteins identified was the histone methyltransferase Smyd1, which we found to be upregulated. Germline deletion of Smyd1 was previously shown to be embryonically lethal, however its role in the adult myocardium is unknown. To determine the role of Smyd1 in the adult heart we generated inducible cardiac-specific Smyd1 knock-out mice (crossing Mer-Cre-Mer mice with those having exons 2 and 3 of smyd1 flanked with loxp sites). Loss of Smyd1 in the adult heart induced fulminate heart failure, commensurate with diminished ejection fraction, LV chamber dilation and myocyte hypertrophy, fetal gene activation and interstitial fibrosis. Loss of Smyd1 also exacerbated hypertrophy and failure in mice subjected to pressure overload. To determine the mechanisms by which Smyd1 regulates cardiac morphology and physiology we performed microarray analysis of ventricular tissue devoid of Smyd1 to establish the pathways influenced by this enzyme; ChIP-PCR was used to validate direct binding of Smyd1 to cardiac genes involved in hypertrophy. We show that endogenous Smyd1 methylated histone H3 on lysine 4 and histone H4 on lysine K20, providing molecular details for how binding of this chromatin remodeler affects gene expression. Importantly, adenoviral-mediated overexpression of Smyd1 inhibited the hypertrophic response (cell growth and gene expression) in neonatal myocytes treated with hypertrophic agonists. These results suggest that Smyd1 functions in the adult myocardium to maintain the differentiated state of the cardiomyocyte and to mitigate disease induced remodeling.
- © 2013 by American Heart Association, Inc.