Epigenetic Regulation of Alternative mRNA Splicing in Dilated Cardiomyopathy.

Weng-Tein Gi,Farbod Sedaghat-Hamedani,Rewati Tappu,Omid Shirvani Samani,Jan Haas,David Hermann Lehmann,Michael Wisdom,Benjamin Meder,Elham Kayvanpour,Hugo A Katus,Andreas Keller

doi:10.3390/jcm9051499

Abstract

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.

Highlights

Dilated cardiomyopathy (DCM) is the predominant heart muscle disease, characterized by a dilatated left ventricle (LV) and reduced contractility
Patients with concomitant valvular heart disease, myocarditis, and inflammatory DCM were excluded from the study after being screened with echocardiography and cardiac magnetic resonance imaging (CMR), and after the myocardial biopsy of the patients were examined histopathologically
The present study utilized an epigenome-wide association approach to examine the interaction between DNA methylome and splicing of the transcriptome in the heart, as both biological processes were only recently shown to play an essential regulatory role in DCM

Summary

Introduction

Dilated cardiomyopathy (DCM) is the predominant heart muscle disease, characterized by a dilatated left ventricle (LV) and reduced contractility. It is associated with high hospitalization rates, sudden cardiac death risk, and substantial demand for heart failure therapies. As the technology of generation sequencing grows expeditiously, causative genetic variants of DCM have been detected in over 30 genes, with a great number of them encoding sarcomere proteins, such as TTN, MYH6, MYH7, and TNNT2, and others encoding proteins constituting calcium or potassium channels, such as SCN5A, proteins essential in the nuclear membrane, such as LMNA, as well as others such as BAG3 or TAZ (G 4.5) [1,5]. Truncating variants in TTN (TTNtv) account for 15%–25% of familial DCM and 10%–18% of sporadic DCM [6]. Most DCM-related genetic variants are reported to be nonsynonymous missense, while other types of mutations, such as frameshifts, insertions, deletions, and splice-site-mutations, were detected [1]

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