Mechanistic basis of neonatal heart regeneration revealed by transcriptome and histone modification profiling

Significance Heart regeneration is restricted to the first week after birth in mice, and the underlying molecular mechanisms remain poorly understood. We compared the transcriptomes and epigenomes of the regenerative and nonregenerative mouse hearts over a 7-d time period after myocardial infarction. We show that injury of the regenerative heart triggers a unique immune response involving a macrophage-secreted factor, CCL24, that promotes regeneration. We also describe a developmental gene program that is active in the regenerative heart, within which we found an RNA-binding protein, IGF2BP3, that enhances regeneration. Our study reveals a detailed blueprint of the transcriptional basis of heart regeneration and represents a resource for the identification of genes that may facilitate cardiac repair in response to injury. 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.

• Publication year

  2019

• Venue

  Proceedings of the National Academy of Sciences of the United States of America

• Publication date

  2019-08-26

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1073/pnas.1905824116PMID 31451669PMCID PMC6744882
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Cardiac Reprogramming Factors Synergistically Activate Genome-wide Cardiogenic Stage-Specific Enhancers.

  2019cited by this paper
• Single-Cell Transcriptional Profiling Reveals Cellular Diversity and Intercommunication in the Mouse Heart.

  2018cited by this paper
• Recognition of RNA N6-methyladenosine by IGF2BP Proteins Enhances mRNA Stability and Translation

  2018influential reference
• Regulation of Cell Cycle to Stimulate Adult Cardiomyocyte Proliferation and Cardiac Regeneration.

  2018cited by this paper
• The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction

  2018cited by this paper
• ENPP2 protects cardiomyocytes from erastin-induced ferroptosis.

  2018cited by this paper
• In Situ Capture of Chromatin Interactions by Biotinylated dCas9.

  2017influential reference
• Multicellular Transcriptional Analysis of Mammalian Heart Regeneration

  2017influential reference
• Heart regeneration and repair after myocardial infarction: translational opportunities for novel therapeutics

  2017cited by this paper
• Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015

  2017cited by this paper
• A Twist2-Dependent Progenitor Cell Contributes to Adult Skeletal Muscle

  2017cited by this paper
• Hippo Pathway Deficiency Reverses Systolic Heart Failure Post-Infarction

  2017cited by this paper
• Single-cut genome editing restores dystrophin expression in a new mouse model of muscular dystrophy

  2017cited by this paper
• Dynamic Control of Enhancer Repertoires Drives Lineage and Stage-Specific Transcription during Hematopoiesis.

  2016influential reference
• RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation.

  2016cited by this paper
• Macrophages and regeneration: Lessons from the heart.

  2016cited by this paper
• Oncostatin M-induced cardiomyocyte dedifferentiation regulates the progression of diabetic cardiomyopathy through B-Raf/Mek/Erk signaling pathway.

  2016cited by this paper
• Mechanisms of Cardiac Regeneration.

  2016cited by this paper
• Myc and cell cycle control.

  2015cited by this paper
• No Evidence for Cardiomyocyte Number Expansion in Preadolescent Mice.

  2015cited by this paper
• Acute inflammation stimulates a regenerative response in the neonatal mouse heart

  2015cited by this paper
• Abstract 261: Foxo4 Promotes Early Inflammatory Response Upon Myocardial Infarction via Endothelial Arg1

  2015cited by this paper
• Nerves Regulate Cardiomyocyte Proliferation and Heart Regeneration.

  2015cited by this paper
• Myocardial NF-κB activation is essential for zebrafish heart regeneration

  2015cited by this paper
• Dynamic changes in the cardiac methylome during postnatal development

  2015cited by this paper
• Macrophages are required for neonatal heart regeneration.

  2014cited by this paper
• Surgical models for cardiac regeneration in neonatal mice

  2014cited by this paper
• Cardiac-Specific YAP Activation Improves Cardiac Function and Survival in an Experimental Murine MI Model

  2014cited by this paper
• Immune modulation of stem cells and regeneration.

  2014cited by this paper
• Regulation of transcription factor activity by interconnected post-translational modifications.

  2014cited by this paper
• Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction.

  2013cited by this paper
• Hippo pathway effector Yap promotes cardiac regeneration

  2013cited by this paper
• B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction

  2013cited by this paper
• An injury-responsive gata4 program shapes the zebrafish cardiac ventricle.

  2013cited by this paper
• Igf Signaling is Required for Cardiomyocyte Proliferation during Zebrafish Heart Development and Regeneration

  2013cited by this paper
• An Integrated Encyclopedia of DNA Elements in the Human Genome

  2012influential reference
• Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family

  2012cited by this paper
• IGF signaling directs ventricular cardiomyocyte proliferation during embryonic heart development

  2011cited by this paper
• Transient Regenerative Potential of the Neonatal Mouse Heart

  2011cited by this paper
• Mechanisms Establishing TLR4-Responsive Activation States of Inflammatory Response Genes

  2011cited by this paper
• Insulin Growth Factor-2 Binding Protein 3 (IGF2BP3) Is a Glioblastoma-specific Marker That Activates Phosphatidylinositol 3-Kinase/Mitogen-activated Protein Kinase (PI3K/MAPK) Pathways by Modulating IGF-2*

  2011cited by this paper
• Inflammasome Activation of Cardiac Fibroblasts Is Essential for Myocardial Ischemia/Reperfusion Injury

  2011cited by this paper
• Cardiomyocyte cell cycle control and growth estimation in vivo--an analysis based on cardiomyocyte nuclei.

  2010cited by this paper
• Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation

  2010cited by this paper
• GREAT improves functional interpretation of cis-regulatory regions

  2010cited by this paper
• The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass.

  2009cited by this paper
• Partial rescue of growth failure in growth hormone (GH)-deficient mice by a single injection of a double-stranded adeno-associated viral vector expressing the GH gene driven by a muscle-specific regulatory cassette.

  2009cited by this paper
• A post-translational modification code for transcription factors: sorting through a sea of signals.

  2009cited by this paper
• Interrelation of immunity and tissue repair or regeneration.

  2009cited by this paper
• Analysis of AAV serotypes 1-9 mediated gene expression and tropism in mice after systemic injection.

  2008cited by this paper
• Integrating cell-signalling pathways with NF-kappaB and IKK function.

  2007cited by this paper
• Macrophage colony-stimulating factor improves cardiac function after ischemic injury by inducing vascular endothelial growth factor production and survival of cardiomyocytes.

  2007cited by this paper
• Integrating cell-signalling pathways with NF-κB and IKK function

  2007cited by this paper
• Thymosin β4 induces adult epicardial progenitor mobilization and neovascularization

  2007cited by this paper
• The RNA-binding Protein IMP-3 Is a Translational Activator of Insulin-like Growth Factor II Leader-3 mRNA during Proliferation of Human K562 Leukemia Cells*

  2005cited by this paper
• Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway.

  2005cited by this paper
• From the Cover: Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

  2005cited by this paper
• Lessons from the heart.

  2000cited by this paper
• Cardiac remodeling--concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling.

  2000cited by this paper
• Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development.

  1996cited by this paper

• IGF2BP3 in Multi-System Diseases: Molecular Mechanisms, Pathological Roles and Translational Insights.

  2026cites this paper
• Enhancer Dynamics for Gene Regulation in the Cardiovascular System.

  2026cites this paper
• Intercellular communication after myocardial infarction: macrophage as the centerpiece.

  2025cites this paper
• PTMA controls cardiomyocyte proliferation and cardiac repair by enhancing STAT3 acetylation

  2025cites this paper
• The Application of scRNA‐Seq in Heart Development and Regeneration

  2025cites this paper
• Functional tendon regeneration is driven by regulatory T cells and IL-33 signaling

  2025cites this paper
• Paracrine IGFBP3 spatially coordinates IGF signaling to induce myocardial regeneration in mice.

  2025cites this paper
• Translational Control in Cardiac Pathophysiology and Therapeutic Development: When mRNA Meets the Heart

  2025cites this paper
• Cardiac macrophages and their functions in homeostasis and injury.

  2025cites this paper
• Hexokinase HK2 regulates the MYH9-GSK3β/β-catenin axis to promote myocardial regeneration and repair after injury.

  2025cites this paper
• Transcriptional regulation in heart development, disease and regeneration: reassessing the fetal gene hypothesis

  2025influential citation
• Heterogeneity and characteristic changes in cardiomyocytes and non-cardiomyocytes following myocardial infarction: Insights from single-cell sequencing analysis (Review)

  2025cites this paper
• Macrophage-Derived CCL24 Promotes Cardiac Fibrosis Via Fibroblast CCR3

  2025cites this paper
• Cardiac lymphatics retain LYVE-1-dependent macrophages during neonatal mouse heart regeneration

  2025cites this paper
• Heart Regeneration and Repair: Molecular Mechanism and Therapeutic Targets

  2025cites this paper
• Organ‐Specific Dedifferentiation and Epigenetic Remodeling in In Vivo Reprogramming

  2025cites this paper
• Maternal milk-derived lipids dictate neonatal macrophage phenotype and function

  2025cites this paper
• The immune system in cardiovascular diseases: from basic mechanisms to therapeutic implications

  2025cites this paper
• Cardiac enhancers: Gateway to the regulatory mechanisms of heart regeneration.

  2025cites this paper
• The epigenetic regulation of crosstalk between cardiac fibroblasts and other cardiac cell types during stress

  2025cites this paper
• Molecular gatekeepers of endogenous adult mammalian cardiomyocyte proliferation

  2025cites this paper
• The transcriptional repressor Ctbp2 as a metabolite sensor regulating cardiomyocytes proliferation and heart regeneration

  2025cites this paper
• Transcriptional, proteomic and metabolic drivers of cardiac regeneration

  2025cites this paper
• Early-age efferocytosis directs macrophage arachidonic acid metabolism for tissue regeneration.

  2025cites this paper
• Cold and hot fibrosis define clinically distinct cardiac pathologies

  2025cites this paper
• Cardiac macrophage: Insights from murine models to translational potential for human studies.

  2025cites this paper
• Coactivator condensation drives cardiovascular cell lineage specification

  2024cites this paper
• Cardiomyocyte‐derived exosomes promote cardiomyocyte proliferation and neonatal heart regeneration

  2024cites this paper
• Recent Insights into Endogenous Mammalian Cardiac Regeneration Post-Myocardial Infarction

  2024cites this paper
• Screening lncRNAs essential for cardiomyocyte proliferation by integrative profiling of lncRNAs and mRNAs associated with heart development.

  2024cites this paper
• Participation of ventricular trabeculae in neonatal cardiac regeneration leads to ectopic recruitment of Purkinje-like cells

  2024cites this paper
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  2024cites this paper
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  2024cites this paper
• Macrophage-derived CCL24 promotes fibrosis and worsens cardiac dysfunction during heart failure

  2024cites this paper
• In situ reprogramming of cardiac fibroblasts into cardiomyocytes in mouse heart with chemicals

  2024cites this paper
• Cardiac Development at a Single-Cell Resolution.

  2024cites this paper
• N-Acetyltransferase 10 represses Uqcr11 and Uqcrb independently of ac4C modification to promote heart regeneration

  2024cites this paper
• The PD-1–PD-L1 pathway maintains an immunosuppressive environment essential for neonatal heart regeneration

  2024cites this paper
• Sphingolipid metabolism controls mammalian heart regeneration.

  2024cites this paper
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  2024cites this paper
• Right ventricular cardiomyocyte expansion accompanies cardiac regeneration in newborn mice after large left ventricular infarcts

  2024cites this paper
• Distinct epicardial gene regulatory programs drive development and regeneration of the zebrafish heart.

  2024cites this paper
• Transcription factor NFYa controls cardiomyocyte metabolism and proliferation during mouse fetal heart development.

  2023cites this paper
• Recent advances in regulating the proliferation or maturation of human-induced pluripotent stem cell-derived cardiomyocytes

  2023cites this paper
• Chemokine CCL2 promotes cardiac regeneration and repair in myocardial infarction mice via activation of the JNK/STAT3 axis

  2023cites this paper
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  2023cites this paper
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  2023cites this paper
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  2023cites this paper
• Quantitative proteomics reveals PPAR signaling pathway regulates the cardiomyocyte activity of neonatal mouse heart

  2023cites this paper
• IGF2BP3 promotes adult myocardial regeneration by stabilizing MMP3 mRNA through interaction with m6A modification

  2023cites this paper
• Comparative genomics analyses reveal sequence determinants underlying interspecies variations in injury-responsive enhancers

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• Cardiomyocyte-fibroblast crosstalk in the postnatal heart

  2023cites this paper
• Malat1 deficiency prevents neonatal heart regeneration by inducing cardiomyocyte binucleation

  2023cites this paper
• The role of cardiac resident macrophage in cardiac aging

  2023cites this paper
• Comparisons between Plant and Animal Stem Cells Regarding Regeneration Potential and Application

  2023cites this paper
• ABRO1 arrests cardiomyocyte proliferation and myocardial repair by suppressing PSPH

  2023cites this paper
• Cardiac regeneration: Options for repairing the injured heart

  2023cites this paper
• Circuit to target approach defines an autocrine myofibroblast loop that drives cardiac fibrosis

  2023cites this paper
• AP-1 signaling modulates cardiac fibroblast stress responses.

  2023cites this paper
• An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair.

  2022cites this paper
• RBPMS is an RNA-binding protein that mediates cardiomyocyte binucleation and cardiovascular development.

  2022cites this paper
• Emerging role of m6A modification in cardiovascular diseases

  2022cites this paper
• Cardiac regeneration following myocardial infarction: the need for regeneration and a review of cardiac stromal cell populations used for transplantation

  2022cites this paper
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  2022cites this paper
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  2022cites this paper
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  2022cites this paper
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  2022cites this paper
• Postnatal expression of cell cycle promoter Fam64a causes heart dysfunction by inhibiting cardiomyocyte differentiation through repression of Klf15

  2022cites this paper
• The cell-autonomous and non-cell-autonomous roles of the Hippo pathway in heart regeneration.

  2022cites this paper
• The Dynamic Role of Cardiac Macrophages in Aging and Disease

  2022cites this paper
• N6-methyladenosine modulates long non-coding RNA in the developing mouse heart

  2022cites this paper
• Emerging roles of the RNA modifications N6-methyladenosine and adenosine-to-inosine in cardiovascular diseases

  2022cites this paper
• Multicellular regulation of miR-196a-5p and miR-425-5 from adipose stem cell-derived exosomes and cardiac repair.

  2022cites this paper
• Resident cardiac macrophages: Heterogeneity and function in health and disease.

  2022cites this paper
• Thymosin β4 and prothymosin α promote cardiac regeneration post-ischaemic injury in mice

  2022cites this paper
• CCL24/CCR3 axis plays a central role in angiotensin II–induced heart failure by stimulating M2 macrophage polarization and fibroblast activation

  2022cites this paper
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  2022cites this paper
• A single-cell comparison of adult and fetal human epicardium defines the age-associated changes in epicardial activity

  2022cites this paper
• Single-cell transcriptomic analysis identifies murine heart molecular features at embryonic and neonatal stages

  2022cites this paper
• The evolving cardiac lymphatic vasculature in development, repair and regeneration

  2021cites this paper
• Genome-wide methylation patterns in Marfan syndrome

  2021cites this paper
• The Diverse Manifestations of Regeneration and Why We Need to Study Them.

  2021cites this paper
• Targeting cardiomyocyte proliferation as a key approach of promoting heart repair after injury

  2021cites this paper
• Microenvironment Stiffness Amplifies Post-ischemia Heart Regeneration in Response to Exogenous Extracellular Matrix Proteins in Neonatal Mice

  2021cites this paper
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  2021cites this paper
• Angiocrine IGFBP3 Spatially Coordinates IGF Signaling During Neonatal Cardiac Regeneration

  2021cites this paper
• Recent Advances in Gene Therapy for Cardiac Tissue Regeneration

  2021cites this paper
• Identification of reference genes for gene expression studies among different developmental stages of murine hearts

  2021cites this paper
• Chemokines in cardiac fibrosis.

  2021cites this paper
• Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance

  2021cites this paper
• Genomic enhancers in cardiac development and disease

  2021cites this paper
• The bright side of fibroblasts: molecular signature and regenerative cues in major organs

  2021cites this paper
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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
• Distinct epicardial gene regulatory programmes drive development and regeneration of the zebrafish heart

  2021cites this paper
• Innate Mechanisms of Heart Regeneration.

  2021cites this paper
• Identi cation of appropriate reference genes for gene expression studies in mice left ventricles from different developmental stages

  2021cites this paper
• Reprogramming adult tendon healing using regenerative neonatal regulatory T cells

  2021cites this paper
• Cardiac regenerative capacity: an evolutionary afterthought?

  2021cites this paper