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Cardiac hypertrophy is the heart's main adaption to hemodynamic stress and can proceed to heart failure as a frequent cause of death. A growing number of molecular mediators has been elucidated, including the phosphatase Calcineurin and its target, the NFAT transcription factors. Additionally, epigenetic transcriptional regulation, such as DNA-methylation is another major, highly conserved layer of regulation in establishing and perpetuating transcription in cardiac hypertrophy and heart failure. We combined whole genome bisulfite sequencing and RNA-sequencing in adult murine cardiac myocytes isolated from Calcineurin-transgenic mice as a model of hypertrophy. We integrated our data on genome-wide DNA methylation and transcription with datasets of cardiac enhancer regions to correlate methylation at enhancers, promoters and gene bodies with transcriptional activity at corresponding sites. Using functional annotation of differentially expressed transcripts and methylated regions, we categorized enriched and potentially novel pathways with a role in cardiac hypertrophy. We identified 7102 differentially methylated regions (DMRs). RNA-sequencing revealed 3395 transcripts which were significantly differentially regulated, 200 of which show a more than twofold higher level of induction or repression, including genes that are known to play a role in cardiac hypertrophy and disease, such as Nppa , Nppb or Myh7. From this list, we validated differential expression of Ror2 , Leprel1 , Vash2 , Apol6 and Barx2 in several different models of cardiac hypertrophy (mechanic stretch, phenylephrine, TAC-surgery) and patient samples of cardiomyopathies. Taken together, we performed an unbiased, genome-wide analysis of the landscape of DNA-methylation and transcription in Calcineurin-transgenic mice. A further characterization of our novel targets seems promising to gain new insights in molecular mechanisms of cardiac muscle disease and may lay on the ground to develop new diagnostic or therapeutic options. [ABSTRACT FROM AUTHOR]