Abstract
DNA methylation is an epigenetic mechanism that controls gene expression. Recent studies of human samples linked dysregulation of DNA methylation to cardiovascular diseases. However, whether DNA methylation is mechanistically involved in disease pathogenesis is unknown. To determine how DNA methylation participates in the development of heart failure, we measured the DNA methylome in healthy and hypertrophic mouse hearts (and in isolated cardiac myocytes in parallel experiments) using reduced representational bisulfite sequencing. Isoproterenol (ISO) minipumps were implanted in two mouse strains with opposite phenotypes: BUB/BnJ, which is resistant to ISO-induced hypertrophy/failure, and BALB/cJ, which is susceptible. DNA and mRNA were isolated from hearts and myocytes and analyzed by bisulfite sequencing and microarrays, respectively. The results reveal three levels of information about the methylome: basal differences between the resistant and susceptible strains, loci affected in a disease-associated manner, and strain-specific changes in methylation following ISO treatment_which serve as novel targets to understand the genetic basis of differential incidence of heart failure. We observed 1,122 loci undergoing a >20% change in methylation after ISO in either strain (p<0.05). Our data also showed significant ISO-induced methylation differences in genes related to myofibril assembly (GO:0031032, p=6e-7) and increased heart weight (MP:0002833, p=2e-6). We selected the top 15,000 promoter-associated CpGs with high variation among samples and carried out an unbiased weighted correlation network analysis (WGCNA) of these methylation data. We identified a module of promoter-associated CpGs whose demethylation is highly correlated with ISO treatment in both strains (75 CpGs, Pearson correlation=0.898, p=0.001). We also identified modules with strain-specific responses to ISO treatment. Interestingly, we found a module of 109 CpGs whose methylation is increased in BALB/cJ strain after ISO treatment, but decreased in BUB/BnJ strain. Our data demonstrate global changes in DNA methylation in the adult heart during the development of disease and reveal networks of modified loci that influence heart failure susceptibility.
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