BACKGROUND: The epigenome refers to marks on the genome, including DNA 
methylation and histone modifications, that regulate the expression of 
underlying genes. A consistent profile of gene expression changes in end-stage 
cardiomyopathy led us to hypothesize that distinct global patterns of the 
epigenome may also exist.
METHODS AND RESULTS: We constructed genome-wide maps of DNA methylation and 
histone-3 lysine-36 trimethylation (H3K36me3) enrichment for cardiomyopathic and 
normal human hearts. More than 506 Mb sequences per library were generated by 
high-throughput sequencing, allowing us to assign methylation scores to ≈28 
million CG dinucleotides in the human genome. DNA methylation was significantly 
different in promoter CpG islands, intragenic CpG islands, gene bodies, and 
H3K36me3-enriched regions of the genome. DNA methylation differences were 
present in promoters of upregulated genes but not downregulated genes. H3K36me3 
enrichment itself was also significantly different in coding regions of the 
genome. Specifically, abundance of RNA transcripts encoded by the DUX4 locus 
correlated to differential DNA methylation and H3K36me3 enrichment. In vitro, 
Dux gene expression was responsive to a specific inhibitor of DNA 
methyltransferase, and Dux siRNA knockdown led to reduced cell viability.
CONCLUSIONS: Distinct epigenomic patterns exist in important DNA elements of the 
cardiac genome in human end-stage cardiomyopathy. The epigenome may control the 
expression of local or distal genes with critical functions in myocardial stress 
response. If epigenomic patterns track with disease progression, assays for the 
epigenome may be useful for assessing prognosis in heart failure. Further 
studies are needed to determine whether and how the epigenome contributes to the 
development of cardiomyopathy.