Next Article in Journal
Contemporary Management of Acute Lower Limb Ischemia: Determinants of Treatment Choice
Previous Article in Journal
Initial Steps for the Development of a Phage-Mediated Gene Replacement Therapy Using CRISPR-Cas9 Technology
Previous Article in Special Issue
Can Circulating Cardiac Biomarkers Be Helpful in the Assessment of LMNA Mutation Carriers?
Open AccessArticle

Epigenetic Regulation of Alternative mRNA Splicing in Dilated Cardiomyopathy

1
Institute for Cardiomyopathies Heidelberg (ICH), Heart Center Heidelberg, University of Heidelberg, 69121 Heidelberg, Germany
2
DZHK (German Center for Cardiovascular Research), 69121 Heidelberg, Germany
3
Department of Medicine III, University of Heidelberg, INF 410, 69120 Heidelberg, Germany
4
Department of Clinical Bioinformatics, Medical Faculty, Saarland University, 66123 Saarbrücken, Germany
5
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(5), 1499; https://doi.org/10.3390/jcm9051499
Received: 10 March 2020 / Revised: 4 May 2020 / Accepted: 12 May 2020 / Published: 16 May 2020
(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)
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. View Full-Text
Keywords: dilated cardiomyopathy; DNA methylation; alternative splicing; epigenetics dilated cardiomyopathy; DNA methylation; alternative splicing; epigenetics
Show Figures

Figure 1

MDPI and ACS Style

Gi, W.-T.; Haas, J.; Sedaghat-Hamedani, F.; Kayvanpour, E.; Tappu, R.; Lehmann, D.H.; Shirvani Samani, O.; Wisdom, M.; Keller, A.; Katus, H.A.; Meder, B. Epigenetic Regulation of Alternative mRNA Splicing in Dilated Cardiomyopathy. J. Clin. Med. 2020, 9, 1499.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop