Abstract
The adult mammalian heart has very limited capacity to regenerate upon injury. Following myocardial infarction, cardiomyocytes are extensively lost and fibroblasts are activated to form a scar, resulting in compromised cardiac function. In contrast, the heart of a neonatal mouse has full capacity to regenerate after myocardial infarction, although such regenerative ability is lost by postnatal (P) day 7. The molecular properties of neonatal hearts that enable regeneration remain unknown. To uncover the mechanisms of neonatal heart regeneration, we induced myocardial infarction (MI) in P1 and P8 hearts, and profiled transcriptomic and epigenomic dynamics by RNA-Seq, H3K27ac ChIP-Seq and H3K27me3 ChIP-Seq at various time points following the surgery. Analysis of differentially expressed genes and groups of enhancers that acquire active status post-MI revealed distinct post-infarction responses between P1 and P8 hearts. Dramatic differences in immune response and developmental gene programs were identified in regenerative P1 versus non-regenerative P8 hearts. Furthermore, we analyzed transcription factors involved in the injury response post MI and constructed gene regulatory networks during neonatal cardiac injury. This work provides insights into the molecular basis of neonatal heart regeneration, and identifies potential genes and cis-regulatory elements that can be modulated to facilitate heart regeneration.
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