Cargando…
Identifying Alternative Hyper-Splicing Signatures in MG-Thymoma by Exon Arrays
BACKGROUND: The vast majority of human genes (>70%) are alternatively spliced. Although alternative pre-mRNA processing is modified in multiple tumors, alternative hyper-splicing signatures specific to particular tumor types are still lacking. Here, we report the use of Affymetrix Human Exon Arra...
Autores principales: | , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2008
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409220/ https://www.ncbi.nlm.nih.gov/pubmed/18545673 http://dx.doi.org/10.1371/journal.pone.0002392 |
_version_ | 1782155739323695104 |
---|---|
author | Soreq, Lilach Gilboa-Geffen, Adi Berrih-Aknin, Sonia Lacoste, Paul Darvasi, Ariel Soreq, Eyal Bergman, Hagai Soreq, Hermona |
author_facet | Soreq, Lilach Gilboa-Geffen, Adi Berrih-Aknin, Sonia Lacoste, Paul Darvasi, Ariel Soreq, Eyal Bergman, Hagai Soreq, Hermona |
author_sort | Soreq, Lilach |
collection | PubMed |
description | BACKGROUND: The vast majority of human genes (>70%) are alternatively spliced. Although alternative pre-mRNA processing is modified in multiple tumors, alternative hyper-splicing signatures specific to particular tumor types are still lacking. Here, we report the use of Affymetrix Human Exon Arrays to spot hyper-splicing events characteristic of myasthenia gravis (MG)-thymoma, thymic tumors which develop in patients with MG and discriminate them from colon cancer changes. METHODOLOGY/PRINCIPAL FINDINGS: We combined GO term to parent threshold-based and threshold-independent ad-hoc functional statistics with in-depth analysis of key modified transcripts to highlight various exon-specific changes. These denote alternative splicing in MG-thymoma tumors compared to healthy human thymus and to in-house and Affymetrix datasets from colon cancer and healthy tissues. By using both global and specific, term-to-parent Gene Ontology (GO) statistical comparisons, our functional integrative ad-hoc method allowed the detection of disease-relevant splicing events. CONCLUSIONS/SIGNIFICANCE: Hyper-spliced transcripts spanned several categories, including the tumorogenic ERBB4 tyrosine kinase receptor and the connective tissue growth factor CTGF, as well as the immune function-related histocompatability gene HLA-DRB1 and interleukin (IL)19, two muscle-specific collagens and one myosin heavy chain gene; intriguingly, a putative new exon was discovered in the MG-involved acetylcholinesterase ACHE gene. Corresponding changes in spliceosome composition were indicated by co-decreases in the splicing factors ASF/SF(2) and SC35. Parallel tumor-associated changes occurred in colon cancer as well, but the majority of the apparent hyper-splicing events were particular to MG-thymoma and could be validated by Fluorescent In-Situ Hybridization (FISH), Reverse Transcription–Polymerase Chain Reaction (RT-PCR) and mass spectrometry (MS) followed by peptide sequencing. Our findings demonstrate a particular alternative hyper-splicing signature for transcripts over-expressed in MG-thymoma, supporting the hypothesis that alternative hyper-splicing contributes to shaping the biological functions of these and other specialized tumors and opening new venues for the development of diagnosis and treatment approaches. |
format | Text |
id | pubmed-2409220 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-24092202008-06-11 Identifying Alternative Hyper-Splicing Signatures in MG-Thymoma by Exon Arrays Soreq, Lilach Gilboa-Geffen, Adi Berrih-Aknin, Sonia Lacoste, Paul Darvasi, Ariel Soreq, Eyal Bergman, Hagai Soreq, Hermona PLoS One Research Article BACKGROUND: The vast majority of human genes (>70%) are alternatively spliced. Although alternative pre-mRNA processing is modified in multiple tumors, alternative hyper-splicing signatures specific to particular tumor types are still lacking. Here, we report the use of Affymetrix Human Exon Arrays to spot hyper-splicing events characteristic of myasthenia gravis (MG)-thymoma, thymic tumors which develop in patients with MG and discriminate them from colon cancer changes. METHODOLOGY/PRINCIPAL FINDINGS: We combined GO term to parent threshold-based and threshold-independent ad-hoc functional statistics with in-depth analysis of key modified transcripts to highlight various exon-specific changes. These denote alternative splicing in MG-thymoma tumors compared to healthy human thymus and to in-house and Affymetrix datasets from colon cancer and healthy tissues. By using both global and specific, term-to-parent Gene Ontology (GO) statistical comparisons, our functional integrative ad-hoc method allowed the detection of disease-relevant splicing events. CONCLUSIONS/SIGNIFICANCE: Hyper-spliced transcripts spanned several categories, including the tumorogenic ERBB4 tyrosine kinase receptor and the connective tissue growth factor CTGF, as well as the immune function-related histocompatability gene HLA-DRB1 and interleukin (IL)19, two muscle-specific collagens and one myosin heavy chain gene; intriguingly, a putative new exon was discovered in the MG-involved acetylcholinesterase ACHE gene. Corresponding changes in spliceosome composition were indicated by co-decreases in the splicing factors ASF/SF(2) and SC35. Parallel tumor-associated changes occurred in colon cancer as well, but the majority of the apparent hyper-splicing events were particular to MG-thymoma and could be validated by Fluorescent In-Situ Hybridization (FISH), Reverse Transcription–Polymerase Chain Reaction (RT-PCR) and mass spectrometry (MS) followed by peptide sequencing. Our findings demonstrate a particular alternative hyper-splicing signature for transcripts over-expressed in MG-thymoma, supporting the hypothesis that alternative hyper-splicing contributes to shaping the biological functions of these and other specialized tumors and opening new venues for the development of diagnosis and treatment approaches. Public Library of Science 2008-06-11 /pmc/articles/PMC2409220/ /pubmed/18545673 http://dx.doi.org/10.1371/journal.pone.0002392 Text en Soreq 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 Soreq, Lilach Gilboa-Geffen, Adi Berrih-Aknin, Sonia Lacoste, Paul Darvasi, Ariel Soreq, Eyal Bergman, Hagai Soreq, Hermona Identifying Alternative Hyper-Splicing Signatures in MG-Thymoma by Exon Arrays |
title | Identifying Alternative Hyper-Splicing Signatures in MG-Thymoma by Exon Arrays |
title_full | Identifying Alternative Hyper-Splicing Signatures in MG-Thymoma by Exon Arrays |
title_fullStr | Identifying Alternative Hyper-Splicing Signatures in MG-Thymoma by Exon Arrays |
title_full_unstemmed | Identifying Alternative Hyper-Splicing Signatures in MG-Thymoma by Exon Arrays |
title_short | Identifying Alternative Hyper-Splicing Signatures in MG-Thymoma by Exon Arrays |
title_sort | identifying alternative hyper-splicing signatures in mg-thymoma by exon arrays |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409220/ https://www.ncbi.nlm.nih.gov/pubmed/18545673 http://dx.doi.org/10.1371/journal.pone.0002392 |
work_keys_str_mv | AT soreqlilach identifyingalternativehypersplicingsignaturesinmgthymomabyexonarrays AT gilboageffenadi identifyingalternativehypersplicingsignaturesinmgthymomabyexonarrays AT berrihakninsonia identifyingalternativehypersplicingsignaturesinmgthymomabyexonarrays AT lacostepaul identifyingalternativehypersplicingsignaturesinmgthymomabyexonarrays AT darvasiariel identifyingalternativehypersplicingsignaturesinmgthymomabyexonarrays AT soreqeyal identifyingalternativehypersplicingsignaturesinmgthymomabyexonarrays AT bergmanhagai identifyingalternativehypersplicingsignaturesinmgthymomabyexonarrays AT soreqhermona identifyingalternativehypersplicingsignaturesinmgthymomabyexonarrays |