Abstract
The neonatal mouse heart has the remarkable capacity to regenerate lost myocardium within the first week of life. Neonatal cardiomyocytes re-express fetal genes that control cell proliferation after injury to promote regeneration. The loss of regenerative capacity of the heart one week after birth coincides with repression of a fetal transcriptional program coordinated by epigenetic regulators. The histone methyltransferase enhancer of zeste homolog 2 (Ezh2) is a repressor of fetal cardiac transcriptional programs and suppresses cardiomyocyte cell proliferation, suggesting a potential function in heart regeneration. However, it was recently demonstrated that Ezh2 is dispensable for heart regeneration in the neonatal heart. Here, we provide evidence supporting this finding and demonstrate that Ezh2 deficiency does not affect regeneration of the neonatal heart. We inactivated Ezh2 in differentiating embryonic cardiomyocytes, which led to depletion of histone H3 trimethylated at lysine 27 (H3K27me3). Ezh2 deficiency in cardiomyocytes did not affect clearance of the fibrotic scar in myocardial infarction (MI) and apical resection models of cardiac injury at post-natal day 1 (P1). Similarly, cardiomyocyte-specific loss of Ezh2 did not affect fibrotic scar size after MI or apical resection at P7, suggesting that it does not extend the regenerative time window. Our results demonstrate that Ezh2 is not required for innate neonatal cardiac regeneration.
Highlights
The adult mammalian heart has limited capacity for regeneration and repair, owing partially to a progressive reduction in cardiomyocyte (CM) proliferative capacity after birth [1,2,3]
We crossed mice carrying LoxP sites flanking exons encoding the catalytic domain of enhancer of zeste homolog 2 (Ezh2) with transgenics expressing the Cre recombinase driven by the myosin heavy chain 6 (Myh6) promoter, which is active since E10.5 [18]
Loss of Ezh2 was confirmed by qPCR, which showed ~65% reduction in mRNA levels in whole ventricles of mutant mice (Fig 1A), consistent with a cardiomyocyte specific loss of Ezh2
Summary
The adult mammalian heart has limited capacity for regeneration and repair, owing partially to a progressive reduction in cardiomyocyte (CM) proliferative capacity after birth [1,2,3]. Minimal CM proliferation in the adult heart leads to limited cardiac muscle regeneration and increased fibrotic scarring in response to cardiac injury, impairing heart function and promoting progression towards heart failure [4]. In response to cardiac injury induced one day after birth (P1), resident CMs revert to a more immature, proliferative state to replenish dead cardiomyocytes [7].
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