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RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns
Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by insufficient levels of the Survival of Motor Neuron (SMN) protein. SMN is expressed ubiquitously and functions in RNA processing pathways that include trafficking of mRNA and assembly of snRNP complexes. Importantly, SMA severity is...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224493/ https://www.ncbi.nlm.nih.gov/pubmed/27557711 http://dx.doi.org/10.1093/nar/gkw731 |
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author | Doktor, Thomas Koed Hua, Yimin Andersen, Henriette Skovgaard Brøner, Sabrina Liu, Ying Hsiu Wieckowska, Anna Dembic, Maja Bruun, Gitte Hoffmann Krainer, Adrian R. Andresen, Brage Storstein |
author_facet | Doktor, Thomas Koed Hua, Yimin Andersen, Henriette Skovgaard Brøner, Sabrina Liu, Ying Hsiu Wieckowska, Anna Dembic, Maja Bruun, Gitte Hoffmann Krainer, Adrian R. Andresen, Brage Storstein |
author_sort | Doktor, Thomas Koed |
collection | PubMed |
description | Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by insufficient levels of the Survival of Motor Neuron (SMN) protein. SMN is expressed ubiquitously and functions in RNA processing pathways that include trafficking of mRNA and assembly of snRNP complexes. Importantly, SMA severity is correlated with decreased snRNP assembly activity. In particular, the minor spliceosomal snRNPs are affected, and some U12-dependent introns have been reported to be aberrantly spliced in patient cells and animal models. SMA is characterized by loss of motor neurons, but the underlying mechanism is largely unknown. It is likely that aberrant splicing of genes expressed in motor neurons is involved in SMA pathogenesis, but increasing evidence indicates that pathologies also exist in other tissues. We present here a comprehensive RNA-seq study that covers multiple tissues in an SMA mouse model. We show elevated U12-intron retention in all examined tissues from SMA mice, and that U12-dependent intron retention is induced upon siRNA knock-down of SMN in HeLa cells. Furthermore, we show that retention of U12-dependent introns is mitigated by ASO treatment of SMA mice and that many transcriptional changes are reversed. Finally, we report on missplicing of several Ca(2+) channel genes that may explain disrupted Ca(2+) homeostasis in SMA and activation of Cdk5. |
format | Online Article Text |
id | pubmed-5224493 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-52244932017-01-17 RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns Doktor, Thomas Koed Hua, Yimin Andersen, Henriette Skovgaard Brøner, Sabrina Liu, Ying Hsiu Wieckowska, Anna Dembic, Maja Bruun, Gitte Hoffmann Krainer, Adrian R. Andresen, Brage Storstein Nucleic Acids Res RNA Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by insufficient levels of the Survival of Motor Neuron (SMN) protein. SMN is expressed ubiquitously and functions in RNA processing pathways that include trafficking of mRNA and assembly of snRNP complexes. Importantly, SMA severity is correlated with decreased snRNP assembly activity. In particular, the minor spliceosomal snRNPs are affected, and some U12-dependent introns have been reported to be aberrantly spliced in patient cells and animal models. SMA is characterized by loss of motor neurons, but the underlying mechanism is largely unknown. It is likely that aberrant splicing of genes expressed in motor neurons is involved in SMA pathogenesis, but increasing evidence indicates that pathologies also exist in other tissues. We present here a comprehensive RNA-seq study that covers multiple tissues in an SMA mouse model. We show elevated U12-intron retention in all examined tissues from SMA mice, and that U12-dependent intron retention is induced upon siRNA knock-down of SMN in HeLa cells. Furthermore, we show that retention of U12-dependent introns is mitigated by ASO treatment of SMA mice and that many transcriptional changes are reversed. Finally, we report on missplicing of several Ca(2+) channel genes that may explain disrupted Ca(2+) homeostasis in SMA and activation of Cdk5. Oxford University Press 2017-01-09 2016-08-23 /pmc/articles/PMC5224493/ /pubmed/27557711 http://dx.doi.org/10.1093/nar/gkw731 Text en © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | RNA Doktor, Thomas Koed Hua, Yimin Andersen, Henriette Skovgaard Brøner, Sabrina Liu, Ying Hsiu Wieckowska, Anna Dembic, Maja Bruun, Gitte Hoffmann Krainer, Adrian R. Andresen, Brage Storstein RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns |
title | RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns |
title_full | RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns |
title_fullStr | RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns |
title_full_unstemmed | RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns |
title_short | RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns |
title_sort | rna-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of u12-dependent introns |
topic | RNA |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224493/ https://www.ncbi.nlm.nih.gov/pubmed/27557711 http://dx.doi.org/10.1093/nar/gkw731 |
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