Abstract 497: Rtf1 Regulates Cardiac Development and Function

Highly regulated transcriptional control of cardiac gene networks is critical for heart development and function. Rtf1 is a critical regulator of multiple transcription processes including elongation and co-transcriptional histone modification. Rtf1 ablation in zebrafish and mice eliminates the cardiac progenitor population, producing embryos without hearts, and knockdown of Rtf1 in neonatal rat ventricular myocytes decreases the expression of sarcomere component genes, suggesting that Rtf1 is indispensable for both establishing the myocardial lineage and maintaining normal physiological homeostasis in differentiated cardiomyocytes. To explore the function of Rtf1 in the adult heart, we generated an inducible knockout of Rtf1 in the adult myocardium. Loss of Rtf1 function in adult cardiomyocytes results in left ventricular systolic dysfunction and pathological features of heart failure. The Rtf1 deficient hearts exhibit a gene expression profile characteristic of heart failure, and display disrupted myofibrils and cell-cell junctions. Intriguingly, and in line with Rtf1’s established role in promoting histone H2B ubiquitination, diminished H2BK120 ubiquitination was also observed in Rtf1 deficient adult hearts. Collectively, our findings show that Rtf1 and Rtf1 mediated H2BK120 ubiquitination are essential epigenetic regulators of both myocardial lineage determination during development as well as maintaining cellular homeostasis, integrity and function in mature cardiomyocytes.