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Background  Recent studies reported altered DNA methylation in failing human hearts. This may suggest a role for  de novo  DNA methylation in the development of heart failure. Here, we tested whether cardiomyocyte-specific loss of  de novo  DNA methyltransferases  Dnmt3a  and  Dnmt3b  altered cardiac function and remodeling after chronic left ventricular pressure overload.    Methods  Mice with specific ablation of  Dnmt3a  and  Dnmt3b  expression in cardiomyocytes were generated by crossing floxed  Dnmt3a fl   and  Dnmt3b fl   alleles with mice expressing Cre recombinase under control of the atrial myosin light chain gene promoter. The efficacy of combined  Dnmt3a/3b  ablation (DKO) was characterized on cardiomyocyte-specific genomic DNA and mRNA levels. Cardiac phenotyping was carried out without (sham) or with left ventricular pressure overload induced by transverse aortic constriction (TAC). Under similar conditions, cardiac genome-wide transcriptional profiling was performed and DNA methylation levels of promoters of differentially regulated genes were assessed by pyrosequencing.    Results  DKO cardiomyocytes showed virtual absence of targeted  Dnmt3a  and  Dnmt3b  mRNA transcripts. Cardiac phenotyping revealed no significant differences between DKO and control mice under sham and TAC conditions. Transcriptome analyses identified upregulation of 44 and downregulation of 9 genes in DKO as compared with control sham mice. TAC mice showed similar changes with substantial overlap of regulated genes compared to sham. Promoters of upregulated genes were largely unmethylated in DKO compared to control mice.    Conclusion  The absence of cardiac pathology in the presence of the predicted molecular phenotype suggests that  de novo  DNA methylation in cardiomyocytes is dispensable for adaptive mechanisms after chronic cardiac pressure overload.

Cardiac Myocyte De Novo DNA Methyltransferases 3a/3b Are Dispensable for Cardiac Function and Remodeling after Chronic Pressure Overload in Mice