Szulik, Marta; Wang, Li; Franklin, Sarah. (University of Utah)
Faculty Advisor: Franklin, Sarah (Medicine, Internal Medicine)
Heart failure (HF) is a type of heart disease characterized by the structural and functional impairment of ventricular filling. In 2016, HF was the underlying cause of death in approximately 78,000 individuals and today more than 6.2 million Americans suffer from heart failure. HF is the final stage for many types of heart disease including cardiac hypertrophy. During hypertrophy, the ventricular walls thicken to help maintain the proper workload needed to continue supplying the body with oxygenated blood. In addition to increase in cell size, cardiac hypertrophy leads to cell death, fibrosis, metabolic reprogramming and reactivation of fetal gene expression. Gene expression is often modulated by changes in chromatin and histone structure via post-translational modifications (PTMs). Histone methylation, a covalent PTM, has been shown to play a significant role in cardiac development.
Smyd1 is a muscle specific lysine histone methyltransferase protein that has a role in early cardiac development and is known to methylate histone H3 on lysine-4. Additionally, loss of Smyd1 in adult mice models has been shown to induce heart failure and hypertrophy whereas overexpression of Smyd1 has been shown to restrict hypertrophic growth in cell model. Although Smyd1 knockdown experiments have been performed in vivo, the effects of knocking down Smyd1 in isolated cardiomyocytes has not been examined. Furthermore, the effects Smyd1 overexpression in adult mammalian heart failure is unknown.
This project seeks to characterize changes in global levels of histone PTM's as a result of either overexpressing or silencing Smyd1. Using proteomic analysis, we have identified the changes in histone methylation and consequently gene expression in the adult heart and isolated cells in response to Smyd1. Our results help us better understand Smyd1 role in the failing heart and help determine it therapeutic potential.