Epigenetic Control of Mammalian Cardiomyocyte Proliferation

Postnatal shutdown of the mammalian cardiomyocyte cell cycle underpins limited regenerative capacity of the adult heart. An epigenetic programme regulates a switch at birth from a proliferative state to functional maturity. Identification of the molecular components regulating this switch has revealed therapeutic opportunities for heart regeneration that have started entering the clinic.

Genome-wide analyses reveal that histone modifications and DNA methylation remodel chromatin in adult cardiomyocytes, downregulating cell cycle activation genes while upregulating maturation genes. Epigenetic regulation of upstream transcriptional pathways (e.g. YAP, WNT and Notch) prevents cell cycle activation in the adult heart. Upregulating glycolysis or suppressing oxidative metabolism enhances cardiac repair following injury, with hypoxia demonstrating safety in humans. Gene therapy techniques enabling myocardial targeting have enhanced the translation of cardiac regenerative therapies, with YAP upregulation paving the way for future trials. The cardiomyocyte cell cycle is regulated by CDKs/cyclins controlled by transcriptional networks that are epigenetically suppressed in the postnatal period. Adult cardiomyocytes also harbour structural barriers and a metabolic state preventing proliferation. Pharmacological and genetic manipulation of these mechanisms can re-activate adult cardiomyocyte proliferation. However, regenerative therapies are challenged by the intrinsic link between proliferation and epigenetics, metabolism, and ultimately cardiac function.