Hypertrophic signaling compensates for contractile and metabolic consequences of DNA methyltransferase 3A loss in human cardiomyocytes

The role of DNA methylation in cardiomyocyte physiology and cardiac disease remains a matter controversy. We have recently provided evidence for an important DNMT3A human cell homeostasis metabolism, using engineered heart tissue (EHT) generated from induced pluripotent stem (hiPSC)-derived cardiomyocytes carrying knockout the de novo methyltransferase DNMT3A. Unlike isogenic control EHT, EHT displayed morphological abnormalities such as lipid accumulations inside associated with impaired mitochondrial well functional defects glucose metabolism. Here, we analyzed setting hypertrophy. hypertrophic signaling by treatment 50 nM endothelin-1 20 μM phenylephrine one week assessed contractility, morphology, methylation, gene expression. While both EHTs controls showed expected activation program, were protected hypertrophy-related impairment. Conversely, prevented metabolic consequences loss DNMT3A, i.e. abolished accumulation likely partial normalization metabolism restored metabolism-related expression EHT. Together, these data suggest not only physiology, but also disease.