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Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT

The epithelial–mesenchymal transition (EMT) is a fundamental developmental process that is abnormally activated in cancer metastasis. Dynamic changes in alternative splicing occur during EMT. ESRP1 and hnRNPM are splicing regulators that promote an epithelial splicing program and a mesenchymal splic...

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Autores principales: Harvey, Samuel E., Xu, Yilin, Lin, Xiaodan, Gao, Xin D., Qiu, Yushan, Ahn, Jaegyoon, Xiao, Xinshu, Cheng, Chonghui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140460/
https://www.ncbi.nlm.nih.gov/pubmed/30042172
http://dx.doi.org/10.1261/rna.066712.118
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author Harvey, Samuel E.
Xu, Yilin
Lin, Xiaodan
Gao, Xin D.
Qiu, Yushan
Ahn, Jaegyoon
Xiao, Xinshu
Cheng, Chonghui
author_facet Harvey, Samuel E.
Xu, Yilin
Lin, Xiaodan
Gao, Xin D.
Qiu, Yushan
Ahn, Jaegyoon
Xiao, Xinshu
Cheng, Chonghui
author_sort Harvey, Samuel E.
collection PubMed
description The epithelial–mesenchymal transition (EMT) is a fundamental developmental process that is abnormally activated in cancer metastasis. Dynamic changes in alternative splicing occur during EMT. ESRP1 and hnRNPM are splicing regulators that promote an epithelial splicing program and a mesenchymal splicing program, respectively. The functional relationships between these splicing factors in the genome scale remain elusive. Comparing alternative splicing targets of hnRNPM and ESRP1 revealed that they coregulate a set of cassette exon events, with the majority showing discordant splicing regulation. Discordant splicing events regulated by hnRNPM show a positive correlation with splicing during EMT; however, concordant events do not, indicating the role of hnRNPM in regulating alternative splicing during EMT is more complex than previously understood. Motif enrichment analysis near hnRNPM–ESRP1 coregulated exons identifies guanine–uridine rich motifs downstream from hnRNPM-repressed and ESRP1-enhanced exons, supporting a general model of competitive binding to these cis-elements to antagonize alternative splicing. The set of coregulated exons are enriched in genes associated with cell migration and cytoskeletal reorganization, which are pathways associated with EMT. Splicing levels of coregulated exons are associated with breast cancer patient survival and correlate with gene sets involved in EMT and breast cancer subtyping. This study identifies complex modes of interaction between hnRNPM and ESRP1 in regulation of splicing in disease-relevant contexts.
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spelling pubmed-61404602019-10-01 Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT Harvey, Samuel E. Xu, Yilin Lin, Xiaodan Gao, Xin D. Qiu, Yushan Ahn, Jaegyoon Xiao, Xinshu Cheng, Chonghui RNA Report The epithelial–mesenchymal transition (EMT) is a fundamental developmental process that is abnormally activated in cancer metastasis. Dynamic changes in alternative splicing occur during EMT. ESRP1 and hnRNPM are splicing regulators that promote an epithelial splicing program and a mesenchymal splicing program, respectively. The functional relationships between these splicing factors in the genome scale remain elusive. Comparing alternative splicing targets of hnRNPM and ESRP1 revealed that they coregulate a set of cassette exon events, with the majority showing discordant splicing regulation. Discordant splicing events regulated by hnRNPM show a positive correlation with splicing during EMT; however, concordant events do not, indicating the role of hnRNPM in regulating alternative splicing during EMT is more complex than previously understood. Motif enrichment analysis near hnRNPM–ESRP1 coregulated exons identifies guanine–uridine rich motifs downstream from hnRNPM-repressed and ESRP1-enhanced exons, supporting a general model of competitive binding to these cis-elements to antagonize alternative splicing. The set of coregulated exons are enriched in genes associated with cell migration and cytoskeletal reorganization, which are pathways associated with EMT. Splicing levels of coregulated exons are associated with breast cancer patient survival and correlate with gene sets involved in EMT and breast cancer subtyping. This study identifies complex modes of interaction between hnRNPM and ESRP1 in regulation of splicing in disease-relevant contexts. Cold Spring Harbor Laboratory Press 2018-10 /pmc/articles/PMC6140460/ /pubmed/30042172 http://dx.doi.org/10.1261/rna.066712.118 Text en © 2018 Harvey et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by the RNA Society for the first 12 months after the full-issue publication date (see http://rnajournal.cshlp.org/site/misc/terms.xhtml). After 12 months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Report
Harvey, Samuel E.
Xu, Yilin
Lin, Xiaodan
Gao, Xin D.
Qiu, Yushan
Ahn, Jaegyoon
Xiao, Xinshu
Cheng, Chonghui
Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT
title Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT
title_full Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT
title_fullStr Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT
title_full_unstemmed Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT
title_short Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT
title_sort coregulation of alternative splicing by hnrnpm and esrp1 during emt
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140460/
https://www.ncbi.nlm.nih.gov/pubmed/30042172
http://dx.doi.org/10.1261/rna.066712.118
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