Abstract
BackgroundRecent 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.MethodsMice with specific ablation of Dnmt3a and Dnmt3b expression in cardiomyocytes were generated by crossing floxed Dnmt3afl and Dnmt3bfl 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.ResultsDKO 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.ConclusionThe 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.
Highlights
Epigenetic mechanisms have evolved as important regulators of development and disease [1,2]
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
Cardiac phenotyping revealed no significant differences between double knockout (DKO) and control
Summary
Epigenetic mechanisms have evolved as important regulators of development and disease [1,2]. High levels of DNA methylation are characteristic for the establishment of somatic cell types with CpG methylation patterns that are highly specific for each cell type [5]. Compared to the established views, postnatal DNA methylation has increasingly emerged to be a dynamic epigenetic feature This holds true for the CpG context as well as for non-CpG methylation in highly specialized somatic cell types such as neurons and cardiomyocytes [7,8]. In the DUX4 gene, which shows increased expression in fascioscapulohumeral muscular dystrophy, a hypermethylated gene body went along with reduced mRNA levels in end-stage failing hearts [10] It is currently unclear whether the observed changes in DNA methylation are causally linked to mechanisms involved in the development of heart failure. 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
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