Genome-wide mRNA expression analyses revealed dysregulation of genes important for cardiomyocyte function in XMlc2-Cre;Dot1L mutants and controls

Epigenetic enzymes play critical roles in embryogenesis by defining higher-order chromatin structures required for the establishment of organ-specific transcriptional networks. In this study we investigated the role of the histone 3 lysine 79 methyltrasferase Dot1L in cardiomyocytes during development. Cardiomyocyte-specific ablation of Dot1L resulted in postnatal lethality with a cardiac phenotype of enlarged, rounded heart with increased ventricular wall thickness and areas of moderate trabeculation postnatally. To understand transciptomic alterations driving the observed phenotype, we conducted RNA-seq experimens in embryonic (E16.5) and neonatal (P1) cardiomyocytes from Dot1L conditional knock out and control mice. Overall, we identified downregulation of genes higly expressed and upregulaton of genes lowly expressed. Genes dowregulated in two critical stages of cardiac development analysed were indicative of defective cardiac patterning during embryogenesis, and defective cell cycle withdrawal in the neonatal period. Overall design: RNA-seq analyses were performed on FACS purified cardiomyocytes from XMlc2-Cre;Dot1L mutant and controls at E16.5 and P1.