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Differential transcript usage in the Parkinson’s disease brain

Studies of differential gene expression have identified several molecular signatures and pathways associated with Parkinson’s disease (PD). The role of isoform switches and differential transcript usage (DTU) remains, however, unexplored. Here, we report the first genome-wide study of DTU in PD. We...

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Autores principales: Dick, Fiona, Nido, Gonzalo S., Alves, Guido Werner, Tysnes, Ole-Bjørn, Nilsen, Gry Hilde, Dölle, Christian, Tzoulis, Charalampos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660910/
https://www.ncbi.nlm.nih.gov/pubmed/33137089
http://dx.doi.org/10.1371/journal.pgen.1009182
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author Dick, Fiona
Nido, Gonzalo S.
Alves, Guido Werner
Tysnes, Ole-Bjørn
Nilsen, Gry Hilde
Dölle, Christian
Tzoulis, Charalampos
author_facet Dick, Fiona
Nido, Gonzalo S.
Alves, Guido Werner
Tysnes, Ole-Bjørn
Nilsen, Gry Hilde
Dölle, Christian
Tzoulis, Charalampos
author_sort Dick, Fiona
collection PubMed
description Studies of differential gene expression have identified several molecular signatures and pathways associated with Parkinson’s disease (PD). The role of isoform switches and differential transcript usage (DTU) remains, however, unexplored. Here, we report the first genome-wide study of DTU in PD. We performed RNA sequencing following ribosomal RNA depletion in prefrontal cortex samples of 49 individuals from two independent case-control cohorts. DTU was assessed using two transcript-count based approaches, implemented in the DRIMSeq and DEXSeq tools. Multiple PD-associated DTU events were detected in each cohort, of which 23 DTU events in 19 genes replicated across both patient cohorts. For several of these, including THEM5, SLC16A1 and BCHE, DTU was predicted to have substantial functional consequences, such as altered subcellular localization or switching to non-protein coding isoforms. Furthermore, genes with PD-associated DTU were enriched in functional pathways previously linked to PD, including reactive oxygen species generation and protein homeostasis. Importantly, the vast majority of genes exhibiting DTU were not differentially expressed at the gene-level and were therefore not identified by conventional differential gene expression analysis. Our findings provide the first insight into the DTU landscape of PD and identify novel disease-associated genes. Moreover, we show that DTU may have important functional consequences in the PD brain, since it is predicted to alter the functional composition of the proteome. Based on these results, we propose that DTU analysis is an essential complement to differential gene expression studies in order to provide a more accurate and complete picture of disease-associated transcriptomic alterations.
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spelling pubmed-76609102020-11-18 Differential transcript usage in the Parkinson’s disease brain Dick, Fiona Nido, Gonzalo S. Alves, Guido Werner Tysnes, Ole-Bjørn Nilsen, Gry Hilde Dölle, Christian Tzoulis, Charalampos PLoS Genet Research Article Studies of differential gene expression have identified several molecular signatures and pathways associated with Parkinson’s disease (PD). The role of isoform switches and differential transcript usage (DTU) remains, however, unexplored. Here, we report the first genome-wide study of DTU in PD. We performed RNA sequencing following ribosomal RNA depletion in prefrontal cortex samples of 49 individuals from two independent case-control cohorts. DTU was assessed using two transcript-count based approaches, implemented in the DRIMSeq and DEXSeq tools. Multiple PD-associated DTU events were detected in each cohort, of which 23 DTU events in 19 genes replicated across both patient cohorts. For several of these, including THEM5, SLC16A1 and BCHE, DTU was predicted to have substantial functional consequences, such as altered subcellular localization or switching to non-protein coding isoforms. Furthermore, genes with PD-associated DTU were enriched in functional pathways previously linked to PD, including reactive oxygen species generation and protein homeostasis. Importantly, the vast majority of genes exhibiting DTU were not differentially expressed at the gene-level and were therefore not identified by conventional differential gene expression analysis. Our findings provide the first insight into the DTU landscape of PD and identify novel disease-associated genes. Moreover, we show that DTU may have important functional consequences in the PD brain, since it is predicted to alter the functional composition of the proteome. Based on these results, we propose that DTU analysis is an essential complement to differential gene expression studies in order to provide a more accurate and complete picture of disease-associated transcriptomic alterations. Public Library of Science 2020-11-02 /pmc/articles/PMC7660910/ /pubmed/33137089 http://dx.doi.org/10.1371/journal.pgen.1009182 Text en © 2020 Dick et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Dick, Fiona
Nido, Gonzalo S.
Alves, Guido Werner
Tysnes, Ole-Bjørn
Nilsen, Gry Hilde
Dölle, Christian
Tzoulis, Charalampos
Differential transcript usage in the Parkinson’s disease brain
title Differential transcript usage in the Parkinson’s disease brain
title_full Differential transcript usage in the Parkinson’s disease brain
title_fullStr Differential transcript usage in the Parkinson’s disease brain
title_full_unstemmed Differential transcript usage in the Parkinson’s disease brain
title_short Differential transcript usage in the Parkinson’s disease brain
title_sort differential transcript usage in the parkinson’s disease brain
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660910/
https://www.ncbi.nlm.nih.gov/pubmed/33137089
http://dx.doi.org/10.1371/journal.pgen.1009182
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