Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 37, Pages 18455-18465Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1905824116
Keywords
transcriptome profiling; epigenome profiling; immune response; myocardial infarction; cardiogenic gene program
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Funding
- NIH [AR-067294, HL-130253, HL-138426, HD-087351]
- Fondation Leducq Transatlantic Networks of Excellence in Cardiovascular Research
- Robert A. Welch Foundation [1-0025]
- American Heart Association
- Harry S. Moss Heart Trust [19PRE34380436]
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The adult mammalian heart has limited capacity for regeneration following injury, whereas the neonatal heart can readily regenerate within a short period after birth. To uncover the molecular mechanisms underlying neonatal heart regeneration, we compared the transcriptomes and epigenomes of regenerative and nonregenerative mouse hearts over a 7-d time period following myocardial infarction injury. By integrating gene expression profiles with histone marks associated with active or repressed chromatin, we identified transcriptional programs underlying neonatal heart regeneration, and the blockade to regeneration in later life. Our results reveal a unique immune response in regenerative hearts and a retained embryonic cardiogenic gene program that is active during neonatal heart regeneration. Among the unique immune factors and embryonic genes associated with cardiac regeneration, we identified Ccl24, which encodes a cytokine, and Igf2bp3, which encodes an RNA-binding protein, as previously unrecognized regulators of cardiomyocyte proliferation. Our data provide insights into the molecular basis of neonatal heart regeneration and identify genes that can be modulated to promote heart regeneration.
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