Key result
DNMT3A knockout impairs cardiomyocyte metabolism and contractility, increasing sensitivity to metabolic stress.
Why the study?
The exact role of DNA methylation in cardiomyocytes remains controversial despite its potential as a therapeutic target in cardiac hypertrophy and heart failure.
DNMT3A-mediated DNA methylation is essential for maintaining cardiomyocyte metabolism and contractility during normal homeostasis and under stress conditions.
BACKGROUND: DNA methylation acts as a mechanism of gene transcription regulation. It has recently gained attention as a possible therapeutic target in cardiac hypertrophy and heart failure. However, its exact role in cardiomyocytes remains controversial. Thus, we knocked out the main de novo DNA methyltransferase in cardiomyocytes, DNMT3A, in human induced pluripotent stem cells. Functional consequences of DNA methylation-deficiency under control and stress conditions were then assessed in human engineered heart tissue from knockout human induced pluripotent stem cell-derived cardiomyocytes. METHODS: was knocked out in human induced pluripotent stem cells by CRISPR/Cas9gene editing. Fibrin-based engineered heart tissue was generated from knockout and control human induced pluripotent stem cell-derived cardiomyocytes. Development and baseline contractility were analyzed by video-optical recording. Engineered heart tissue was subjected to different stress protocols, including serum starvation, serum variation, and restrictive feeding. Molecular, histological, and ultrastructural analyses were performed afterward. RESULTS: in human cardiomyocytes had three main consequences for cardiomyocyte morphology and function: (1) Gene expression changes of contractile proteins such as higher atrial gene expression and lower MYH7/MYH6 ratio correlated with different contraction kinetics in knockout versus wild-type; (2) Aberrant activation of the glucose/lipid metabolism regulator peroxisome proliferator-activated receptor gamma was associated with accumulation of lipid vacuoles within knockout cardiomyocytes; (3) Hypoxia-inducible factor 1α protein instability was associated with impaired glucose metabolism and lower glycolytic enzyme expression, rendering knockout-engineered heart tissue sensitive to metabolic stress such as serum withdrawal and restrictive feeding. CONCLUSION: The results suggest an important role of DNA methylation in the normal homeostasis of cardiomyocytes and during cardiac stress, which could make it an interesting target for cardiac therapy.
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Madsen et al. (2020) studied Cardiac hypertrophy and heart failure. DNMT3A knockout vs. Control/wild-type cardiomyocytes was evaluated on Cardiomyocyte morphology and function under control and stress conditions. DNMT3A knockout in human cardiomyocytes altered contraction kinetics, caused lipid accumulation, and impaired glucose metabolism, increasing sensitivity to metabolic stress.
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