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Multiplexed functional genomic analysis of 5’ untranslated region mutations across the spectrum of prostate cancer
The functional consequences of genetic variants within 5’ untranslated regions (UTRs) on a genome-wide scale are poorly understood in disease. Here we develop a high-throughput multi-layer functional genomics method called PLUMAGE (Pooled full-length UTR Multiplex Assay on Gene Expression) to quanti...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270899/ https://www.ncbi.nlm.nih.gov/pubmed/34244513 http://dx.doi.org/10.1038/s41467-021-24445-6 |
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author | Lim, Yiting Arora, Sonali Schuster, Samantha L. Corey, Lukas Fitzgibbon, Matthew Wladyka, Cynthia L. Wu, Xiaoying Coleman, Ilsa M. Delrow, Jeffrey J. Corey, Eva True, Lawrence D. Nelson, Peter S. Ha, Gavin Hsieh, Andrew C. |
author_facet | Lim, Yiting Arora, Sonali Schuster, Samantha L. Corey, Lukas Fitzgibbon, Matthew Wladyka, Cynthia L. Wu, Xiaoying Coleman, Ilsa M. Delrow, Jeffrey J. Corey, Eva True, Lawrence D. Nelson, Peter S. Ha, Gavin Hsieh, Andrew C. |
author_sort | Lim, Yiting |
collection | PubMed |
description | The functional consequences of genetic variants within 5’ untranslated regions (UTRs) on a genome-wide scale are poorly understood in disease. Here we develop a high-throughput multi-layer functional genomics method called PLUMAGE (Pooled full-length UTR Multiplex Assay on Gene Expression) to quantify the molecular consequences of somatic 5’ UTR mutations in human prostate cancer. We show that 5’ UTR mutations can control transcript levels and mRNA translation rates through the creation of DNA binding elements or RNA-based cis-regulatory motifs. We discover that point mutations can simultaneously impact transcript and translation levels of the same gene. We provide evidence that functional 5’ UTR mutations in the MAP kinase signaling pathway can upregulate pathway-specific gene expression and are associated with clinical outcomes. Our study reveals the diverse mechanisms by which the mutational landscape of 5’ UTRs can co-opt gene expression and demonstrates that single nucleotide alterations within 5’ UTRs are functional in cancer. |
format | Online Article Text |
id | pubmed-8270899 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82708992021-07-23 Multiplexed functional genomic analysis of 5’ untranslated region mutations across the spectrum of prostate cancer Lim, Yiting Arora, Sonali Schuster, Samantha L. Corey, Lukas Fitzgibbon, Matthew Wladyka, Cynthia L. Wu, Xiaoying Coleman, Ilsa M. Delrow, Jeffrey J. Corey, Eva True, Lawrence D. Nelson, Peter S. Ha, Gavin Hsieh, Andrew C. Nat Commun Article The functional consequences of genetic variants within 5’ untranslated regions (UTRs) on a genome-wide scale are poorly understood in disease. Here we develop a high-throughput multi-layer functional genomics method called PLUMAGE (Pooled full-length UTR Multiplex Assay on Gene Expression) to quantify the molecular consequences of somatic 5’ UTR mutations in human prostate cancer. We show that 5’ UTR mutations can control transcript levels and mRNA translation rates through the creation of DNA binding elements or RNA-based cis-regulatory motifs. We discover that point mutations can simultaneously impact transcript and translation levels of the same gene. We provide evidence that functional 5’ UTR mutations in the MAP kinase signaling pathway can upregulate pathway-specific gene expression and are associated with clinical outcomes. Our study reveals the diverse mechanisms by which the mutational landscape of 5’ UTRs can co-opt gene expression and demonstrates that single nucleotide alterations within 5’ UTRs are functional in cancer. Nature Publishing Group UK 2021-07-09 /pmc/articles/PMC8270899/ /pubmed/34244513 http://dx.doi.org/10.1038/s41467-021-24445-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Lim, Yiting Arora, Sonali Schuster, Samantha L. Corey, Lukas Fitzgibbon, Matthew Wladyka, Cynthia L. Wu, Xiaoying Coleman, Ilsa M. Delrow, Jeffrey J. Corey, Eva True, Lawrence D. Nelson, Peter S. Ha, Gavin Hsieh, Andrew C. Multiplexed functional genomic analysis of 5’ untranslated region mutations across the spectrum of prostate cancer |
title | Multiplexed functional genomic analysis of 5’ untranslated region mutations across the spectrum of prostate cancer |
title_full | Multiplexed functional genomic analysis of 5’ untranslated region mutations across the spectrum of prostate cancer |
title_fullStr | Multiplexed functional genomic analysis of 5’ untranslated region mutations across the spectrum of prostate cancer |
title_full_unstemmed | Multiplexed functional genomic analysis of 5’ untranslated region mutations across the spectrum of prostate cancer |
title_short | Multiplexed functional genomic analysis of 5’ untranslated region mutations across the spectrum of prostate cancer |
title_sort | multiplexed functional genomic analysis of 5’ untranslated region mutations across the spectrum of prostate cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270899/ https://www.ncbi.nlm.nih.gov/pubmed/34244513 http://dx.doi.org/10.1038/s41467-021-24445-6 |
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