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.

Public Health Relevance

Heart disease is the leading cause of death in the United States, however, therapeutic options are lacking to combat this deadly condition. This application seeks to advance our understanding of the cellular changes occurring in the heart during disease and identify novel therapeutic targets. Specifically this proposal will utilize a novel genetic model and state-of-the-art proteomics and next generation sequencing technology to determine the role of a myocyte-specific histone methyltransferase in regulating pathological remodeling.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL130424-04
Application #
9625520
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Wong, Renee P
Project Start
2016-01-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Tracy, Christopher; Warren, Junco S; Szulik, Marta et al. (2018) The Smyd Family of Methyltransferases: Role in Cardiac and Skeletal Muscle Physiology and Pathology. Curr Opin Physiol 1:140-152
Warren, Junco S; Tracy, Christopher M; Miller, Mickey R et al. (2018) Histone methyltransferase Smyd1 regulates mitochondrial energetics in the heart. Proc Natl Acad Sci U S A 115:E7871-E7880
Franklin, Sarah; Kimball, Todd; Rasmussen, Tara L et al. (2016) The chromatin-binding protein Smyd1 restricts adult mammalian heart growth. Am J Physiol Heart Circ Physiol 311:H1234-H1247