Genomic structural variations lead to dysregulation of important coding and non-coding RNA species in dilated cardiomyopathy.

Tanja Weis,Stefan Mester,Carsten Dietrich,Maximilian Wuerstle,Tobias Rausch,Alan Lai,Daniel Oehler,Sebastian Buss,Derliz Mereles,Jan O. Korbel ,Hugo A. Katus ,Jes‐Niels Boeckel,Diana Bordalo ,Benjamin Meder,Andreas Keller,Elham Kayvanpour,Daniel Benjamin Holzer ,Ali Amr,Farbod Sedaghat‐Hamedani,Rouven Nietsch,Andreas E. Posch ,Avisha Carstensen,Karen Frese ,Dietmar Pils,Emil Wirsz,Jan Haas,Eva Riechert,Mirko Völkers

doi:10.15252/emmm.201707838

Abstract

The transcriptome needs to be tightly regulated by mechanisms that include transcription factors, enhancers, and repressors as well as non‐coding RNAs. Besides this dynamic regulation, a large part of phenotypic variability of eukaryotes is expressed through changes in gene transcription caused by genetic variation. In this study, we evaluate genome‐wide structural genomic variants (SVs) and their association with gene expression in the human heart. We detected 3,898 individual SVs affecting all classes of gene transcripts (e.g., mRNA, miRNA, lncRNA) and regulatory genomic regions (e.g., enhancer or TFBS). In a cohort of patients (n = 50) with dilated cardiomyopathy (DCM), 80,635 non‐protein‐coding elements of the genome are deleted or duplicated by SVs, containing 3,758 long non‐coding RNAs and 1,756 protein‐coding transcripts. 65.3% of the SV‐eQTLs do not harbor a significant SNV‐eQTL, and for the regions with both classes of association, we find similar effect sizes. In case of deleted protein‐coding exons, we find downregulation of the associated transcripts, duplication events, however, do not show significant changes over all events. In summary, we are first to describe the genomic variability associated with SVs in heart failure due to DCM and dissect their impact on the transcriptome. Overall, SVs explain up to 7.5% of the variation of cardiac gene expression, underlining the importance to study human myocardial gene expression in the context of the individual genome. This has immediate implications for studies on basic mechanisms of cardiac maladaptation, biomarkers, and (gene) therapeutic studies alike.

Highlights

The myocardium has to permanently adapt to changes in the hemodynamic demand (Heusch et al, 2014), aging of the organism (Boon et al, 2013), and multiple external stressors (Ware et al, 2016)
Metabolic, or inflammatory stimuli, cardiac remodeling is triggered to compensate for a molecular misbalance. If such adaptive processes fail, for example, due to pathogenic gene mutations, heart failure is the ultimate endpoint in a self-perpetuating, pathogenic vicious circle (Heusch et al, 2014)
While the role of single nucleotide polymorphisms (SNPs) is quite well established in heart failure of different causes, virtually nothing is known about the contribution of structural genomic variations on myocardial gene expression in human disease states

Summary

Introduction

The myocardium has to permanently adapt to changes in the hemodynamic demand (Heusch et al, 2014), aging of the organism (Boon et al, 2013), and multiple external stressors (Ware et al, 2016). The coordination of these cascades involving cardiac energy metabolism, calcium handling, contractile elements, or protein turnover is not well understood, but executed by changes in gene transcription or protein translation (Correll et al, 2015; Nickel et al, 2015; Anderson et al, 2016; Mizushima et al, 2016; Tuomainen & Tavi, 2017). While yet little is known about the impact of these variations on the cardiac transcriptome and consecutively phenotype, first pilot studies could link single nucleotide polymorphisms (SNPs) and cardiac gene expression (Koopmann et al, 2014)

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Conclusion