Dynamic DNA methylation orchestrates cardiomyocyte development, maturation and disease

Ralf Gilsbach, Sebastian Preissl, Björn A. Grüning, Tilman Schnick, Lukas Burger, Vladimir Benes, Andreas Würch, Ulrike Bönisch, Stefan Günther, Rolf Backofen, Bernd K. Fleischmann, Dirk Schübeler and Lutz Hein ()
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Ralf Gilsbach: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg
Sebastian Preissl: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg
Björn A. Grüning: Bioinformatics Group, University of Freiburg
Tilman Schnick: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg
Lukas Burger: Friedrich Miescher Institute for Biomedical Research
Vladimir Benes: European Molecular Biology Laboratory, Genomics Core Facility
Andreas Würch: Max Planck Institute of Immunobiology and Epigenetics
Ulrike Bönisch: Max Planck Institute of Immunobiology and Epigenetics
Stefan Günther: Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences, University of Freiburg
Rolf Backofen: Bioinformatics Group, University of Freiburg
Bernd K. Fleischmann: Institute of Physiology I, Life and Brain Center, University of Bonn
Dirk Schübeler: Friedrich Miescher Institute for Biomedical Research
Lutz Hein: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6288

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