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Transcriptome Sequencing Revealed Significant Alteration of Cortical Promoter Usage and Splicing in Schizophrenia

BACKGROUND: While hybridization based analysis of the cortical transcriptome has provided important insight into the neuropathology of schizophrenia, it represents a restricted view of disease-associated gene activity based on predetermined probes. By contrast, sequencing technology can provide un-b...

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Autores principales: Wu, Jing Qin, Wang, Xi, Beveridge, Natalie J., Tooney, Paul A., Scott, Rodney J., Carr, Vaughan J., Cairns, Murray J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338678/
https://www.ncbi.nlm.nih.gov/pubmed/22558445
http://dx.doi.org/10.1371/journal.pone.0036351
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author Wu, Jing Qin
Wang, Xi
Beveridge, Natalie J.
Tooney, Paul A.
Scott, Rodney J.
Carr, Vaughan J.
Cairns, Murray J.
author_facet Wu, Jing Qin
Wang, Xi
Beveridge, Natalie J.
Tooney, Paul A.
Scott, Rodney J.
Carr, Vaughan J.
Cairns, Murray J.
author_sort Wu, Jing Qin
collection PubMed
description BACKGROUND: While hybridization based analysis of the cortical transcriptome has provided important insight into the neuropathology of schizophrenia, it represents a restricted view of disease-associated gene activity based on predetermined probes. By contrast, sequencing technology can provide un-biased analysis of transcription at nucleotide resolution. Here we use this approach to investigate schizophrenia-associated cortical gene expression. METHODOLOGY/PRINCIPAL FINDINGS: The data was generated from 76 bp reads of RNA-Seq, aligned to the reference genome and assembled into transcripts for quantification of exons, splice variants and alternative promoters in postmortem superior temporal gyrus (STG/BA22) from 9 male subjects with schizophrenia and 9 matched non-psychiatric controls. Differentially expressed genes were then subjected to further sequence and functional group analysis. The output, amounting to more than 38 Gb of sequence, revealed significant alteration of gene expression including many previously shown to be associated with schizophrenia. Gene ontology enrichment analysis followed by functional map construction identified three functional clusters highly relevant to schizophrenia including neurotransmission related functions, synaptic vesicle trafficking, and neural development. Significantly, more than 2000 genes displayed schizophrenia-associated alternative promoter usage and more than 1000 genes showed differential splicing (FDR<0.05). Both types of transcriptional isoforms were exemplified by reads aligned to the neurodevelopmentally significant doublecortin-like kinase 1 (DCLK1) gene. CONCLUSIONS: This study provided the first deep and un-biased analysis of schizophrenia-associated transcriptional diversity within the STG, and revealed variants with important implications for the complex pathophysiology of schizophrenia.
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spelling pubmed-33386782012-05-03 Transcriptome Sequencing Revealed Significant Alteration of Cortical Promoter Usage and Splicing in Schizophrenia Wu, Jing Qin Wang, Xi Beveridge, Natalie J. Tooney, Paul A. Scott, Rodney J. Carr, Vaughan J. Cairns, Murray J. PLoS One Research Article BACKGROUND: While hybridization based analysis of the cortical transcriptome has provided important insight into the neuropathology of schizophrenia, it represents a restricted view of disease-associated gene activity based on predetermined probes. By contrast, sequencing technology can provide un-biased analysis of transcription at nucleotide resolution. Here we use this approach to investigate schizophrenia-associated cortical gene expression. METHODOLOGY/PRINCIPAL FINDINGS: The data was generated from 76 bp reads of RNA-Seq, aligned to the reference genome and assembled into transcripts for quantification of exons, splice variants and alternative promoters in postmortem superior temporal gyrus (STG/BA22) from 9 male subjects with schizophrenia and 9 matched non-psychiatric controls. Differentially expressed genes were then subjected to further sequence and functional group analysis. The output, amounting to more than 38 Gb of sequence, revealed significant alteration of gene expression including many previously shown to be associated with schizophrenia. Gene ontology enrichment analysis followed by functional map construction identified three functional clusters highly relevant to schizophrenia including neurotransmission related functions, synaptic vesicle trafficking, and neural development. Significantly, more than 2000 genes displayed schizophrenia-associated alternative promoter usage and more than 1000 genes showed differential splicing (FDR<0.05). Both types of transcriptional isoforms were exemplified by reads aligned to the neurodevelopmentally significant doublecortin-like kinase 1 (DCLK1) gene. CONCLUSIONS: This study provided the first deep and un-biased analysis of schizophrenia-associated transcriptional diversity within the STG, and revealed variants with important implications for the complex pathophysiology of schizophrenia. Public Library of Science 2012-04-27 /pmc/articles/PMC3338678/ /pubmed/22558445 http://dx.doi.org/10.1371/journal.pone.0036351 Text en Wu 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Wu, Jing Qin
Wang, Xi
Beveridge, Natalie J.
Tooney, Paul A.
Scott, Rodney J.
Carr, Vaughan J.
Cairns, Murray J.
Transcriptome Sequencing Revealed Significant Alteration of Cortical Promoter Usage and Splicing in Schizophrenia
title Transcriptome Sequencing Revealed Significant Alteration of Cortical Promoter Usage and Splicing in Schizophrenia
title_full Transcriptome Sequencing Revealed Significant Alteration of Cortical Promoter Usage and Splicing in Schizophrenia
title_fullStr Transcriptome Sequencing Revealed Significant Alteration of Cortical Promoter Usage and Splicing in Schizophrenia
title_full_unstemmed Transcriptome Sequencing Revealed Significant Alteration of Cortical Promoter Usage and Splicing in Schizophrenia
title_short Transcriptome Sequencing Revealed Significant Alteration of Cortical Promoter Usage and Splicing in Schizophrenia
title_sort transcriptome sequencing revealed significant alteration of cortical promoter usage and splicing in schizophrenia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338678/
https://www.ncbi.nlm.nih.gov/pubmed/22558445
http://dx.doi.org/10.1371/journal.pone.0036351
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