Heart failure is the leading cause of death in developed countries and is characterized by myocyte growth, fibrosis and organ remodeling, and is accompanied by transcriptional changes in the myocyte genome. These global changes in gene expression, which constitute both adaptive and maladaptive reprogramming, are driven by structural changes in chromatin. Although many epigenetic factors have been identified that influence these transcriptional changes, the proteins responsible for regulating chromatin and their subsequent effects on cellular and organ remodeling during heart disease are largely unknown. One key mechanism to alter chromatin structure is through histone modifications and early studies utilizing histone deacetylase inhibitors revealed that heart disease progression could be attenuated upon treatment in animal models, although the ubiquitous expression of these proteins and the non-specific nature of the inhibitors has made them unfeasible as a therapeutic tool in the heart, thus far. In contrast, Smyd1, is a unique myocyte-specific histone methyltransferase that regulates gene expression in the cardiomyocyte. It was originally shown to play a role in early cardiac development, however more recently, we have determined that Smyd1 is differentially regulated in human heart failure patients and in mouse models of heart disease. In addition, we have demonstrated that loss of Smyd1 in the adult mouse heart leads to pro-hypertrophic signaling resulting in myocyte growth, fibrosis and functional decline. Additionally, we examined the two Smyd1 isoforms, Smyd1a and Smyd1b, in isolated myocytes and showed that Smyd1a overexpression was capable of inhibiting phenylephrine-induced hypertrophy. To build upon this work I will (Aim 1) determine if overexpression of Smyd1a in the heart is able to inhibit disease-induced remodeling using a novel transgenic mouse model, and (Aim 2) identify the specific genes modified by Smyd1 in the genome to regulate hypertrophic signaling in the myocardium using chromatin immunoprecipitation and next-generation DNA sequencing (ChIP-Seq). This proposal will allow me to determine the function of Smyd1 in the adult heart, evaluate its role in attenuating heart disease and identify the molecular mechanisms by which myocyte growth is regulated. Overall these experiments will enhance our understanding of how global changes in chromatin remodeling are coordinated and how they affect cardiac phenotype during the development of heart disease.
Today more than 6.5 million Americans live with heart failure and it is estimated that by 2030 this number will increase to 8 million people. While this deadly condition contributes to 25% of all deaths in the USA there are few therapeutics interventions to combat it. Our studies will evaluate the ability of Smyd1a to attenuate disease-induced remodeling in the myocardium as a potential target of future therapeutic interventions.
