Mechanisms of Cardiac Myosin Heavy Chain Gene Regulation

Sarcomeres are the fundamental functional unit of contractility in cardiomyocytes (and the heart) and consist of two major contractile myofilament protein complexes: thick myosin and thin actin filaments. Myosin heavy chain (MYH) proteins function as the molecular motors that produce sliding between these thick and thin myofilaments, resulting in sarcomere contractility. MYH6 and MYH7 serve as the primary myosin heavy chain proteins and are antithetically expressed at significantly different ratios according to cardiomyocyte cell type and state (developmental and disease). Under cardiac stress and pathophysiological conditions including heart failure, adult ventricular cardiomyocytes respond by decreasing MYH6 while increasing MYH7. Because MYH6 displays greater ATPase activity and actin sliding velocity than MYH7, these changes in the ratio of MYH6 to MYH7 expression can have significant effects on cardiac contractility and correlate with a decline in cardiac performance. However, hearts expressing higher levels of MYH6 to such heart failure/cardiac stress conditions exhibit improved responses. Thus, altering the levels of these cardiac MYH proteins can result in significant contractility changes that can profoundly impact overall heart function. Consequently, we propose to investigate and discover the underlying gene regulatory mechanisms that control the antithetical expression of MYH6 and MYH7 and their isoform switching. Toward this end, a multi-disciplinary approach will be used to: (1) investigate key cis-regulatory sequences that regulate MYH6-MYH7 promoter competition for a cardiac MYH locus control region, (2) identify trans-acting factors that may regulate MYH6-MYH7 promoter competition for a cardiac MYH locus control region, and (3) investigate whether altering MYH6-MYH7 gene expression can be used to modify cardiac disease in hPSC-cardiomyopathy models. Project Number: 1R01HL178857-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Neil Chi | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $761,152 | Activity Code: R01 | Study Section: Basic Biology of Blood, Heart and Vasculature Study Section [BBHV] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17885701