KMT2D regulates specific programs in heart development via histone H3 lysine 4 dimethylation

Histone modifying genes involved in histone H3 lysine 4 (H3K4) methylation are critical for heart development, but the roles of these genes are not well understood. Here, we demonstrate a requirement for the H3K4 methyltransferase KMT2D in cardiac precursors and cardiomyocytes during cardiogenesis. Gene expression analysis revealed upregulation of hypoxia response genes, as well as downregulation of ion transport and cell cycle genes, leading to altered calcium handling and cell cycle defects. We further determined that myocardial Kmt2d deletion led to decreased H3K4me2 at promoters and enhancers. Finally, we identified KMT2D binding regions in cardiomyocytes, of which a subset was associated with decreased gene expression and decreased H3K4me2 in mutant hearts. This subset included genes related to ion transport, hypoxia-reoxygenation and cell cycle regulation, suggesting that KMT2D is important for these processes. Our findings indicate that KMT2D is essential for regulating cardiac gene expression during heart development via H3K4 dimethylation. Examination of H3K4me1, H3K4me2 and H3K4me3 in E11.5 mouse embryonic hearts.