title: Dynamic changes in the cardiac methylome during postnatal development.
abstract: Relatively little is known about the epigenetic control mechanisms that guide postnatal organ maturation. The goal of this study was to determine whether DNA methylation plays an important role in guiding transcriptional changes during the first 2 wk of mouse heart development, which is an important period for cardiomyocyte maturation, loss of proliferative capacity and loss of regenerative potential. Gene expression profiling (RNA-seq) and genome-wide sequencing of methylated DNA (MBD-seq) identified dynamic changes in the cardiac methylome during postnatal development [2545 differentially methylated regions (DMRs) from P1 to P14 in the mouse]. The vast majority (~80%) of DMRs were hypermethylated between P1 and P14, and these hypermethylated regions were associated with transcriptional shut down of important developmental signaling pathways, including Hedgehog, bone morphogenetic protein, TGF-β, fibroblast growth factor, and Wnt/β-catenin signaling. Postnatal inhibition of DNA methylation with 5-aza-2'-deoxycytidine induced a marked increase (~3-fold) in cardiomyocyte proliferation and ~50% reduction in the percentage of binucleated cardiomyocytes compared with saline-treated controls. This study provides novel evidence for widespread alterations in DNA methylation during postnatal heart maturation and suggests that cardiomyocyte cell cycle arrest during the neonatal period is subject to regulation by DNA methylation.
authors.affiliation: *School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia; and Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Choon Boon
authors.initials: CB
authors.lastname: Sim
authors.affiliation: *School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia; and Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Ziemann
authors.affiliation: *School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia; and Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Antony
authors.initials: A
authors.lastname: Kaspi
authors.affiliation: *School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia; and Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: K N
authors.initials: KN
authors.lastname: Harikrishnan
authors.affiliation: *School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia; and Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Jenny
authors.initials: J
authors.lastname: Ooi
authors.affiliation: *School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia; and Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Ishant
authors.initials: I
authors.lastname: Khurana
authors.affiliation: *School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia; and Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Lisa
authors.initials: L
authors.lastname: Chang
authors.affiliation: *School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia; and Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: James E
authors.initials: JE
authors.lastname: Hudson
authors.affiliation: *School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia; and Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia assam.el-osta@bakeridi.edu.au e.porrello@uq.edu.au.
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
authors.affiliation: *School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia; and Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia assam.el-osta@bakeridi.edu.au e.porrello@uq.edu.au.
authors.forename: Enzo R
authors.initials: ER
authors.lastname: Porrello
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D059447:Cell Cycle Checkpoints; D057846:Cell-Penetrating Peptides; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000254:growth & development*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D057846:Cell-Penetrating Peptides; D000077209:Decitabine; D001374:Azacitidine
keywords: DNA methylation; binucleation; cardiomyocyte proliferation; epigenetics; neonatal heart