Abstract
Epigenetic mechanisms such as microRNA and histone modification are crucially responsible for dysregulated gene expression in heart failure. In contrast, the role of DNA methylation, another well-characterized epigenetic mark, is unknown. In order to examine whether human cardiomyopathy of different etiologies are connected by a unifying pattern of DNA methylation pattern, we undertook profiling with ischaemic and idiopathic end-stage cardiomyopathic left ventricular (LV) explants from patients who had undergone cardiac transplantation compared to normal control. We performed a preliminary analysis using methylated-DNA immunoprecipitation-chip (MeDIP-chip), validated differential methylation loci by bisulfite-(BS) PCR and high throughput sequencing, and identified 3 angiogenesis-related genetic loci that were differentially methylated. Using quantitative RT-PCR, we found that the expression of these genes differed significantly between CM hearts and normal control (p<0.01). Moreover, for each individual LV tissue, differential methylation showed a predicted correlation to differential expression of the corresponding gene. Thus, differential DNA methylation exists in human cardiomyopathy. In this series of heterogenous cardiomyopathic LV explants, differential DNA methylation was found in at least 3 angiogenesis-related genes. While in other systems, changes in DNA methylation at specific genomic loci usually precede changes in the expression of corresponding genes, our current findings in cardiomyopathy merit further investigation to determine whether DNA methylation changes play a causative role in the progression of heart failure.
Highlights
The pathogenesis of heart failure involves molecular mechanisms which are becoming better understood [1,2] and studies in both experimental models and humans demonstrate the important relevance of dysregulated gene expression [1,3]
Differential methylation of CpG islands is part of the epigenetic variation found in humans [18,27]
Consistent with previous observations correlating gene expression with DNA methylation [9,10,11], we have found that hypermethylation within the 59 region of the PECAM1 gene correlated with its reduced expression in different cardiac samples
Summary
The pathogenesis of heart failure involves molecular mechanisms which are becoming better understood [1,2] and studies in both experimental models and humans demonstrate the important relevance of dysregulated gene expression [1,3]. Transcriptomic analyses of human dilated cardiomyopathy show a consistent and distinct pattern of gene expression [4], and dysregulated expression of both coding and non-coding genes directly affects heart failure development and progression [3,5] Higher order mechanisms such as microRNA [5,6] and histone modifications [7,8] can alter gene expression control in cardiovascular disease, without involving any change in the underlying DNA sequence. Complementary to this, one of the most important findings in the field of epigenetics in recent times is the discovery of DNA methylation variation between individuals at a genome-wide level [15]. At least through its control of gene expression, DNA methylation variation may account for complex disease susceptibility or progression [15,18]
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