Abstract 247: Rtf1 Controls Sarcomere Integrity and Cardiac Function

Abstract

Sarcomere integrity must be continuously maintained in cardiomyocytes to ensure contractile function; however, the genetic programs controlling this process are not completely understood. We have previously shown that the RNA polymerase II associated protein Rtf1 directs cardiac progenitor cell formation during early cardiogenesis. Here we report that in mature cardiomyocytes, Rtf1 controls gene programs essential for the maintenance of sarcomere structure and cardiac function. Cardiomyocyte-specific ablation of Rtf1 in mice results in dilated cardiomyopathy characterized by thinning of the myocardial walls, dilation of the ventricular cavity and impaired left ventricle contractile function. Rtf1 knockdown in neonatal rat ventricular myocytes model results in the breakdown of sarcomeres and downregulation of myofibrillar gene programs accompanied by reduced abundance of monoubiquitinated H2BK120 and epigenetic marks associated with actively transcribed genes. In zebrafish embryos, mutation in Rtf1’s histone modification domain arrests cardiomyocyte differentiation and heart tube formation. Together these findings demonstrate that Rtf1 controls cardiomyocyte maturation, myofibril integrity and cardiac function by modulating cardiac epigenetic landscapes.