In recent years, the genetic architecture of dilated cardiomyopathy (DCM) has been
more thoroughly elucidated. However, there is still insufficient knowledge on the modifiers and
regulatory principles that lead to the failure of myocardial function. The current study investigates the
association of epigenome-wide DNA methylation and alternative splicing, both of which are important
regulatory principles in DCM. We analyzed screening and replication cohorts of cases and controls
and identified distinct transcriptomic patterns in the myocardium that differ significantly, and we
identified a strong association of intronic DNA methylation and flanking exons usage (p < 2 × 10−16).
By combining differential exon usage (DEU) and differential methylation regions (DMR), we found
a significant change of regulation in important sarcomeric and other DCM-associated pathways.
Interestingly, inverse regulation of Titin antisense non-coding RNA transcript splicing and DNA
methylation of a locus reciprocal to TTN substantiate these findings and indicate an additional role
for non-protein-coding transcripts. In summary, this study highlights for the first time the close
interrelationship between genetic imprinting by DNA methylation and the transport of this epigenetic
information towards the dynamic mRNA splicing landscape. This expands our knowledge of the
genome–environment interaction in DCM besides simple gene expression regulation