Dataset Information

Alterations in cardiac DNA methylation in human dilated cardiomyopathy.

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.

SUBMITTER: Haas J

PROVIDER: S-EPMC3598081 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Alterations in cardiac DNA methylation in human dilated cardiomyopathy.

Haas Jan J Frese Karen S KS Park Yoon Jung YJ Keller Andreas A Vogel Britta B Lindroth Anders M AM Weichenhan Dieter D Franke Jennifer J Fischer Simon S Bauer Andrea A Marquart Sabine S Sedaghat-Hamedani Farbod F Kayvanpour Elham E Köhler Doreen D Wolf Nadine M NM Hassel Sarah S Nietsch Rouven R Wieland Thomas T Ehlermann Philipp P Schultz Jobst-Hendrik JH Dösch Andreas A Mereles Derliz D Hardt Stefan S Backs Johannes J Hoheisel Jörg D JD Plass Christoph C Katus Hugo A HA Meder Benjamin B

EMBO molecular medicine 20130122 3

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 ...[more]

PMID: 23341106

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Project description:RATIONALE:LMNA (Lamin A/C), a nuclear membrane protein, interacts with genome through lamin-associated domains (LADs) and regulates gene expression. Mutations in the LMNA gene cause a diverse array of diseases, including dilated cardiomyopathy (DCM). DCM is the leading cause of death in laminopathies. OBJECTIVE:To identify LADs and characterize their associations with CpG methylation and gene expression in human cardiac myocytes in DCM. METHODS AND RESULTS:LMNA chromatin immunoprecipitation-sequencing, reduced representative bisulfite sequencing, and RNA-sequencing were performed in 5 control and 5 LMNA-associated DCM hearts. LADs were identified using enriched domain detector program. Genome-wide 331±77 LADs with an average size of 2.1±1.5 Mbp were identified in control human cardiac myocytes. LADs encompassed ≈20% of the genome and were predominantly located in the heterochromatin and less so in the promoter and actively transcribed regions. LADs were redistributed in DCM as evidenced by a gain of 520 and loss of 149 genomic regions. Approximately, 4500 coding genes and 800 long noncoding RNAs, whose levels correlated with the transcript levels of coding genes in cis, were differentially expressed in DCM. TP53 (tumor protein 53) was the most prominent among the dysregulated pathways. CpG sites were predominantly hypomethylated genome-wide in controls and DCM hearts, but overall CpG methylation was increased in DCM. LADs were associated with increased CpG methylation and suppressed gene expression. Integrated analysis identified genes whose expressions were regulated by LADs or CpG methylation, or by both, the latter pertained to genes involved in cell death, cell cycle, and metabolic regulation. CONCLUSIONS:LADs encompass ≈20% of the genome in human cardiac myocytes comprised several hundred coding and noncoding genes. LADs are redistributed in LMNA-associated DCM in association with markedly altered CpG methylation and gene expression. Thus, LADs through genomic alterations contribute to the pathogenesis of DCM in laminopathies.

Dataset Information

Alterations in cardiac DNA methylation in human dilated cardiomyopathy.

Publications

Alterations in cardiac DNA methylation in human dilated cardiomyopathy.

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