Research Article: Differential DNA Methylation Correlates with Differential Expression of Angiogenic Factors in Human Heart Failure

Date Published: January 13, 2010

Publisher: Public Library of Science

Author(s): Mehregan Movassagh, Mun-Kit Choy, Martin Goddard, Martin R. Bennett, Thomas A. Down, Roger S.-Y. Foo, Michael Polymenis.

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.

Partial Text: 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]. Furthermore, 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].

In eukaryotes, DNA methylation occurs by the addition of a methyl group to the carbon 5′ position of the nucleotide cytosine ring, and cytosine methylation in mammals, is found most commonly in the context of the sequence 5′-CG-3′, which is also referred to as a CpG dinucleotide. In the mammalian genome, an estimated 70% of all CpGs are methylated [27]. Unmethylated CpG on the other hand are largely grouped in clusters called “CpG islands” in the 5′ regulatory region of many genes. The frequency of CpG dinucleotides in “CpG islands” is higher than is found in other DNA regions. Notably, differential methylation of CpG islands is part of the epigenetic variation found in humans [18], [27].



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