ABSTRACT: Postnatal maturation of cardiomyocytes is characterized by a metabolic switch from glycolysis to fatty acid oxidation (FAO), chromatin reconfiguration, and exit from cell cycle, instating a barrier for adult heart regeneration. To explore whether metabolic reprogramming overcomes this barrier and enables heart regeneration, we abrogate FAO in cardiomyocytes by inactivation of Cpt1b. We find that disablement of FAO in cardiomyocytes improves resistance to hypoxia and stimulates cardiomyocyte proliferation, allowing heart regeneration after ischemia/reperfusion injury. Metabolic studies reveal profound changes in energy metabolism and accumulation of α-ketoglutarate in Cpt1b-mutant cardiomyocytes, leading to activation of the α-ketoglutarate-dependent lysine demethylase KDM5. Activated KDM5 demethylates broad H3K4me3 domains in genes driving cardiomyocyte maturation, lowering transcription and shifting cardiomyocytes into a less mature state, thereby promoting proliferation. We conclude that metabolic maturation shapes the epigenetic landscape of cardiomyocytes, creating a roadblock for further cell divisions. Reversal of this process allows repair of damaged hearts.
This repository holds all the scripts that were used to analyze the data sets described in this study. We used prior published software for all calculations and all visualizations. The repository is divided into separate folders containing miscellaneous scripts (misc) and code specific to data types (RNA/ChIP-Seq).