Regulation of cardiac hypertrophy and failure by the histone methyltransferase Smyd1

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Cardiac hypertrophy, a common precursor to heart failure, is a compensatory response to an increased workload characterized by myocyte growth. Hypertrophic cardiomyocytes undergo significant changes in cellular plasticity by adopting the expression profile and some phenotypic aspects of fetal cardiac cells. This phenomenon represents the molecular underpinnings driving the morphological and physiological remodeling in heart disease and likely includes both maladaptive and compensatory mechanisms aimed at mitigating disease-induced remodeling. To execute these changes in gene expression, chromatin structure must undergo significant alterations to silence or activate select regions of the genome. Recent studies in murine models of cardiac hypertrophy have demonstrated that modulating key epigenetic factors can inhibit these gene expression changes and prevent pathologic remodeling; however, our knowledge of the chromatin modifiers driving cardiac disease is quite limited. Smyd1, a myocyte-specific histone methyltransferase, was originally identified as a necessary regulator of cardiac development in constitutive Smyd1 knockout mice, which die in utero due to cardiac defects. More recently, we have shown that Smyd1 expression is differentially regulated during pressure overload hypertrophy and failure in mice (consistent with its expression in humans) and that it controls pathologic gene expression and myocyte growth in the adult heart. Most intriguing, data from isolated myocytes show that over-expression of the Smyd1a variant can inhibit disease induced remodeling, suggesting this pathway may hold promise for therapeutic targeting. Despite these findings, very little is known regarding Smyd1's molecular function in the adult myocardium. This application will leverage a unique genetic animal model and state-of-the-art proteomic and next- generation sequencing technologies to conceptually advance our understanding of heart failure. Specifically, this work will determine if Smyd1a can inhibit growth and pathologic remodeling in an animal model of hypertrophy and failure and identify the factors governing Smyd1's activity, genomic targeting and functional variance. In addition this work will conclusively determine how Smyd1 regulates growth in the myocardium by identifying the genes bound by Smyd1 variants, and investigate how binding affects transcription. This approach will reveal discrete molecular mechanisms governing pathologic growth, but moreover, it has the potential to provide paradigm changing insights into how histone methyltransferases regulate chromatin structure and thereby cardiac phenotype. Ultimately, characterizing the components of this novel, myocyte-specific signaling pathway could reveal new therapeutic targets for heart failure.