title: Dynamic DNA methylation orchestrates cardiomyocyte development, maturation and disease.
abstract: The heart is a highly specialized organ with essential function for the organism throughout life. The significance of DNA methylation in shaping the phenotype of the heart remains only partially known. Here we generate and analyse DNA methylomes from highly purified cardiomyocytes of neonatal, adult healthy and adult failing hearts. We identify large genomic regions that are differentially methylated during cardiomyocyte development and maturation. Demethylation of cardiomyocyte gene bodies correlates strongly with increased gene expression. Silencing of demethylated genes is characterized by the polycomb mark H3K27me3 or by DNA methylation. De novo methylation by DNA methyltransferases 3A/B causes repression of fetal cardiac genes, including essential components of the cardiac sarcomere. Failing cardiomyocytes partially resemble neonatal methylation patterns. This study establishes DNA methylation as a highly dynamic process during postnatal growth of cardiomyocytes and their adaptation to pathological stress in a process tightly linked to gene regulation and activity.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gilsbach
authors.affiliation: 1] Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany [2] Hermann Staudinger Graduate School, University of Freiburg, Albertstrasse 21, 79104 Freiburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Preissl
authors.affiliation: 1] Bioinformatics Group, Department of Computer Science, University of Freiburg, Georges-Köhler-Allee 106, 79110 Freiburg, Germany [2] Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences, University of Freiburg, Hermann-Herder-Strasse 9, 79104 Freiburg, Germany.
authors.forename: Björn A
authors.initials: BA
authors.lastname: Grüning
authors.affiliation: 1] Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany [2] University Heart Center Freiburg/Bad Krozingen, Department of Congenital Heart Defects and Paediatric Cardiology, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Schnick
authors.affiliation: 1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland [2] Swiss Institute of Bioinformatics, Maulbeerstrasse 66, 4058 Basel, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Burger
authors.affiliation: European Molecular Biology Laboratory, Genomics Core Facility, Meyerhofstraße 1, 69117 Heidelberg, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Benes
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Würch
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bönisch
authors.affiliation: Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences, University of Freiburg, Hermann-Herder-Strasse 9, 79104 Freiburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Günther
authors.affiliation: Bioinformatics Group, Department of Computer Science, University of Freiburg, Georges-Köhler-Allee 106, 79110 Freiburg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Backofen
authors.affiliation: Institute of Physiology I, Life and Brain Center, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
authors.forename: Bernd K
authors.initials: BK
authors.lastname: Fleischmann
authors.affiliation: 1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland [2] University of Basel, Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schübeler
authors.affiliation: 1] Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany [2] BIOSS Centre for Biological Signalling Studies, University of Freiburg, Schänzlestrasse 18, 79104 Freiburg, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Hein
mesh_terms: D000818:Animals; D001665:Binding Sites; D002318:Cardiovascular Diseases / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D018899:CpG Islands; D004247:DNA / Q000737:chemistry; D019175:DNA Methylation; D004452:Echocardiography; D053595:Embryonic Stem Cells / Q000166:cytology; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006321:Heart / Q000196:embryology; D006657:Histones / Q000737:chemistry; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic
chemical_list: D006657:Histones; D004247:DNA