Alterations in cardiac DNA methylation in human dilated cardiomyopathy

Jan Haas, Karen S. Frese, Yoon Jung Park, Andreas Keller, Britta Vogel, Anders M. Lindroth, Dieter Weichenhan, Jennifer Franke, Simon Fischer, Andrea Bauer, Sabine Marquart, Farbod Sedaghat-Hamedani, Elham Kayvanpour, Doreen Köhler, Nadine M. Wolf, Sarah Hassel, Rouven Nietsch, Thomas Wieland, Philipp Ehlermann, Jobst Hendrik SchultzAndreas Dösch, Derliz Mereles, Stefan Hardt, Johannes Backs, Jörg D. Hoheisel, Christoph Plass, Hugo A. Katus, Benjamin Meder

Research output: Contribution to journalArticlepeer-review

151 Scopus citations

Abstract

Dilated cardiomyopathies (DCM) show remarkable variability in their age of onset, phenotypic presentation, and clinical course. Hence, disease mechanisms must exist that modify the occurrence and progression of DCM, either by genetic or epigenetic factors that may interact with environmental stimuli. In the present study, we examined genome-wide cardiac DNA methylation in patients with idiopathic DCM and controls. We detected methylation differences in pathways related to heart disease, but also in genes with yet unknown function in DCM or heart failure, namely Lymphocyte antigen 75 (LY75), Tyrosine kinase-type cell surface receptor HER3 (ERBB3), Homeobox B13 (HOXB13) and Adenosine receptor A2A (ADORA2A). Mass-spectrometric analysis and bisulphite-sequencing enabled confirmation of the observed DNA methylation changes in independent cohorts. Aberrant DNA methylation in DCM patients was associated with significant changes in LY75 and ADORA2A mRNA expression, but not in ERBB3 and HOXB13. In vivo studies of orthologous ly75 and adora2a in zebrafish demonstrate a functional role of these genes in adaptive or maladaptive pathways in heart failure. Dilated cardiomyopathy is one the most frequent heart muscle diseases, which is responsible for one third of all heart failure cases. Here, the authors show widespread changes in DNA methylation patterns responsible for the disease.

Original languageEnglish
Pages (from-to)413-429
Number of pages17
JournalEMBO Molecular Medicine
Volume5
Issue number3
DOIs
StatePublished - Mar 2013

Keywords

  • Biomarker
  • DNA methylation
  • Dilated cardiomyopathy
  • Epigenetics
  • Heart failure

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