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Cis-regulatory mutations associate with transcriptional and post-transcriptional deregulation of gene regulatory programs in cancers
Most cancer alterations occur in the noncoding portion of the human genome, where regulatory regions control gene expression. The discovery of noncoding mutations altering the cells’ regulatory programs has been limited to few examples with high recurrence or high functional impact. Here, we show th...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9757053/ https://www.ncbi.nlm.nih.gov/pubmed/36477895 http://dx.doi.org/10.1093/nar/gkac1143 |
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author | Castro-Mondragon, Jaime A Aure, Miriam Ragle Lingjærde, Ole Christian Langerød, Anita Martens, John W M Børresen-Dale, Anne-Lise Kristensen, Vessela N Mathelier, Anthony |
author_facet | Castro-Mondragon, Jaime A Aure, Miriam Ragle Lingjærde, Ole Christian Langerød, Anita Martens, John W M Børresen-Dale, Anne-Lise Kristensen, Vessela N Mathelier, Anthony |
author_sort | Castro-Mondragon, Jaime A |
collection | PubMed |
description | Most cancer alterations occur in the noncoding portion of the human genome, where regulatory regions control gene expression. The discovery of noncoding mutations altering the cells’ regulatory programs has been limited to few examples with high recurrence or high functional impact. Here, we show that transcription factor binding sites (TFBSs) have similar mutation loads to those in protein-coding exons. By combining cancer somatic mutations in TFBSs and expression data for protein-coding and miRNA genes, we evaluate the combined effects of transcriptional and post-transcriptional alterations on the regulatory programs in cancers. The analysis of seven TCGA cohorts culminates with the identification of protein-coding and miRNA genes linked to mutations at TFBSs that are associated with a cascading trans-effect deregulation on the cells’ regulatory programs. Our analyses of cis-regulatory mutations associated with miRNAs recurrently predict 12 mature miRNAs (derived from 7 precursors) associated with the deregulation of their target gene networks. The predictions are enriched for cancer-associated protein-coding and miRNA genes and highlight cis-regulatory mutations associated with the dysregulation of key pathways associated with carcinogenesis. By combining transcriptional and post-transcriptional regulation of gene expression, our method predicts cis-regulatory mutations related to the dysregulation of key gene regulatory networks in cancer patients. |
format | Online Article Text |
id | pubmed-9757053 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-97570532022-12-19 Cis-regulatory mutations associate with transcriptional and post-transcriptional deregulation of gene regulatory programs in cancers Castro-Mondragon, Jaime A Aure, Miriam Ragle Lingjærde, Ole Christian Langerød, Anita Martens, John W M Børresen-Dale, Anne-Lise Kristensen, Vessela N Mathelier, Anthony Nucleic Acids Res Computational Biology Most cancer alterations occur in the noncoding portion of the human genome, where regulatory regions control gene expression. The discovery of noncoding mutations altering the cells’ regulatory programs has been limited to few examples with high recurrence or high functional impact. Here, we show that transcription factor binding sites (TFBSs) have similar mutation loads to those in protein-coding exons. By combining cancer somatic mutations in TFBSs and expression data for protein-coding and miRNA genes, we evaluate the combined effects of transcriptional and post-transcriptional alterations on the regulatory programs in cancers. The analysis of seven TCGA cohorts culminates with the identification of protein-coding and miRNA genes linked to mutations at TFBSs that are associated with a cascading trans-effect deregulation on the cells’ regulatory programs. Our analyses of cis-regulatory mutations associated with miRNAs recurrently predict 12 mature miRNAs (derived from 7 precursors) associated with the deregulation of their target gene networks. The predictions are enriched for cancer-associated protein-coding and miRNA genes and highlight cis-regulatory mutations associated with the dysregulation of key pathways associated with carcinogenesis. By combining transcriptional and post-transcriptional regulation of gene expression, our method predicts cis-regulatory mutations related to the dysregulation of key gene regulatory networks in cancer patients. Oxford University Press 2022-12-08 /pmc/articles/PMC9757053/ /pubmed/36477895 http://dx.doi.org/10.1093/nar/gkac1143 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Computational Biology Castro-Mondragon, Jaime A Aure, Miriam Ragle Lingjærde, Ole Christian Langerød, Anita Martens, John W M Børresen-Dale, Anne-Lise Kristensen, Vessela N Mathelier, Anthony Cis-regulatory mutations associate with transcriptional and post-transcriptional deregulation of gene regulatory programs in cancers |
title | Cis-regulatory mutations associate with transcriptional and post-transcriptional deregulation of gene regulatory programs in cancers |
title_full | Cis-regulatory mutations associate with transcriptional and post-transcriptional deregulation of gene regulatory programs in cancers |
title_fullStr | Cis-regulatory mutations associate with transcriptional and post-transcriptional deregulation of gene regulatory programs in cancers |
title_full_unstemmed | Cis-regulatory mutations associate with transcriptional and post-transcriptional deregulation of gene regulatory programs in cancers |
title_short | Cis-regulatory mutations associate with transcriptional and post-transcriptional deregulation of gene regulatory programs in cancers |
title_sort | cis-regulatory mutations associate with transcriptional and post-transcriptional deregulation of gene regulatory programs in cancers |
topic | Computational Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9757053/ https://www.ncbi.nlm.nih.gov/pubmed/36477895 http://dx.doi.org/10.1093/nar/gkac1143 |
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