Abstract 17818: Epigenomic Profiling Reveals DNA Methylation Changes Associated with Hypertrophic Cardiomyopathy
Objective: DNA methylation is indispensable for vertebrate genome function. Abnormal DNA methylation have been implicated in the end-stage failing human heart. Hypertrophic cardiomyopathy is a an important substrate for heart failure. Up to date, however, few data are available about DNA methylation in hypertrophic cardiomyopathy.
Methods: Tissue was obtained from routine myotomy-myectomy cardiac operation on hypertrophic obstructive cardiomyopathy (HOCM) patients. Array based genome-wide methylation analysis and gene expression profiling were performed on a panel of ventricular septal tissues from six HOCM patients and five health controls.
Results: DNA methylation was significantly different in promoter CpG islands, intragenic CpG islands and gene bodies between HOCM patients and health controls. The overall methylation patterns could significantly distinguish HOCM from health controls and the main reason is hypomethylation of the genome. Among 1,870 differentially methylated CpG sites (FDR-adjusted p<0.05), 1,534 (82%) were hypomethylated. These differentially hypomethylated CpG sites covered 850 unique genes, which were highly enriched for focal adhesion and ECM-receptor interaction (p<8.0E-04). Transcriptome data demonstrated that a total of 365 genes were significantly up-regulated and 221 genes were significantly down-regulated among HOCM tissues (FDR-adjusted p<0.05, foldchange>1.5). Interestingly, the significantly upregulated gene set was also highly enriched among functional categories involved in focal adhesion and ECM-receptor interaction (p<1.0E-06). By integrating of the normalized gene expression and DNA methylation gene lists, we identified 54 genes that were both significantly hypomethylated and up-regulated within hypertrophied myocardial tissue.
Conclusion: Our preliminary study offers the first evidence that distinct DNA methylation is associated with hypertrophic cardiomyopathy. This DNA methylation changes are relevant to the expression of critical genes involving in cardiac remodeling. As hypertrophic cardiomyopathy is often caused by sarcomere protein mutations, future studies investigating how the epigenetic mechanism responses to genetic mutation should be pursued.
- © 2012 by American Heart Association, Inc.