Rtf1 transcriptionally regulates neonatal and adult cardiomyocyte biology

The PAF1 complex component Rtf1 is an RNA Polymerase II-interacting transcription regulatory protein that promotes transcription elongation and the co-transcriptional monoubiquitination of histone 2B. Rtf1 plays an essential role in the specification of cardiac progenitors from the lateral plate mesoderm during early embryogenesis, but its requirement in mature cardiac cells is unknown. We investigated the importance of Rtf1 in neonatal and adult cardiomyocytes using knockdown and knockout approaches. Loss of Rtf1 activity in neonatal cardiomyocytes disrupted cell morphology and resulted in a breakdown of sarcomeres. Similarly, Rtf1 ablation in mature cardiomyocytes of the adult mouse heart led to myofibril disorganization, disrupted cell-cell junctions, fibrosis, and systolic dysfunction. Rtf1 knockout hearts eventually failed and exhibited structural and gene expression defects resembling dilated cardiomyopathy. Intriguingly, we observed that loss of Rtf1 activity caused a rapid change in the expression of key cardiac structural and functional genes in both neonatal and adult cardiomyocytes, suggesting that Rtf1 is continuously required to support expression of the cardiac gene program. This BioProject contains RNA-seq data from control and Rtf1 inducible knockout left ventricles after 1, 2, and 3 weeks of Rtf1 knockout by ad libitum feeding of tamoxifen chow.