Genomic structural variations lead to dysregulation of important coding and non-coding RNA species in dilated cardiomyopathy. Haas, J., Mester, S., Lai, A., Frese, K. S, Sedaghat-Hamedani, F., Kayvanpour, E., Rausch, T., Nietsch, R., Boeckel, J., Carstensen, A., Völkers, M., Dietrich, C., Pils, D., Amr, A., Holzer, D. B, Martins Bordalo, D., Oehler, D., Weis, T., Mereles, D., Buss, S., Riechert, E., Wirsz, E., Wuerstle, M., Korbel, J. O, Keller, A., Katus, H. A, Posch, A. E, & Meder, B. EMBO molecular medicine, 10:107–120, January, 2018. doi abstract bibtex 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 ( = 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.
@Article{Haas2018,
author = {Haas, Jan and Mester, Stefan and Lai, Alan and Frese, Karen S and Sedaghat-Hamedani, Farbod and Kayvanpour, Elham and Rausch, Tobias and Nietsch, Rouven and Boeckel, Jes-Niels and Carstensen, Avisha and Völkers, Mirko and Dietrich, Carsten and Pils, Dietmar and Amr, Ali and Holzer, Daniel B and Martins Bordalo, Diana and Oehler, Daniel and Weis, Tanja and Mereles, Derliz and Buss, Sebastian and Riechert, Eva and Wirsz, Emil and Wuerstle, Maximilian and Korbel, Jan O and Keller, Andreas and Katus, Hugo A and Posch, Andreas E and Meder, Benjamin},
title = {Genomic structural variations lead to dysregulation of important coding and non-coding RNA species in dilated cardiomyopathy.},
journal = {EMBO molecular medicine},
year = {2018},
volume = {10},
pages = {107--120},
month = jan,
issn = {1757-4684},
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 ( = 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.},
country = {England},
doi = {10.15252/emmm.201707838},
issn-linking = {1757-4676},
issue = {1},
keywords = {cardiac transcriptome; dilated cardiomyopathy; expression quantitative trait locus; genomic structural variation; heart failure},
nlm-id = {101487380},
owner = {NLM},
pii = {emmm.201707838},
pmc = {PMC5760848},
pmid = {29138229},
pubmodel = {Print},
pubstatus = {ppublish},
revised = {2018-01-11},
}
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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 ( = 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. 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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 ( = 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. 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