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Human papillomavirus integration transforms chromatin to drive oncogenesis
BACKGROUND: Human papillomavirus (HPV) drives almost all cervical cancers and up to 70% of head and neck cancers. Frequent integration into the host genome occurs predominantly in tumorigenic types of HPV. We hypothesize that changes in chromatin state at the location of integration can result in ch...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10294493/ https://www.ncbi.nlm.nih.gov/pubmed/37365652 http://dx.doi.org/10.1186/s13059-023-02926-9 |
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author | Karimzadeh, Mehran Arlidge, Christopher Rostami, Ariana Lupien, Mathieu Bratman, Scott V. Hoffman, Michael M. |
author_facet | Karimzadeh, Mehran Arlidge, Christopher Rostami, Ariana Lupien, Mathieu Bratman, Scott V. Hoffman, Michael M. |
author_sort | Karimzadeh, Mehran |
collection | PubMed |
description | BACKGROUND: Human papillomavirus (HPV) drives almost all cervical cancers and up to 70% of head and neck cancers. Frequent integration into the host genome occurs predominantly in tumorigenic types of HPV. We hypothesize that changes in chromatin state at the location of integration can result in changes in gene expression that contribute to the tumorigenicity of HPV. RESULTS: We find that viral integration events often occur along with changes in chromatin state and expression of genes near the integration site. We investigate whether introduction of new transcription factor binding sites due to HPV integration could invoke these changes. Some regions within the HPV genome, particularly the position of a conserved CTCF binding site, show enriched chromatin accessibility signal. ChIP-seq reveals that the conserved CTCF binding site within the HPV genome binds CTCF in 4 HPV(+) cancer cell lines. Significant changes in CTCF binding pattern and increases in chromatin accessibility occur exclusively within 100 kbp of HPV integration sites. The chromatin changes co-occur with out-sized changes in transcription and alternative splicing of local genes. Analysis of The Cancer Genome Atlas (TCGA) HPV(+) tumors indicates that HPV integration upregulates genes which have significantly higher essentiality scores compared to randomly selected upregulated genes from the same tumors. CONCLUSIONS: Our results suggest that introduction of a new CTCF binding site due to HPV integration reorganizes chromatin state and upregulates genes essential for tumor viability in some HPV(+) tumors. These findings emphasize a newly recognized role of HPV integration in oncogenesis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-023-02926-9. |
format | Online Article Text |
id | pubmed-10294493 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-102944932023-06-28 Human papillomavirus integration transforms chromatin to drive oncogenesis Karimzadeh, Mehran Arlidge, Christopher Rostami, Ariana Lupien, Mathieu Bratman, Scott V. Hoffman, Michael M. Genome Biol Research BACKGROUND: Human papillomavirus (HPV) drives almost all cervical cancers and up to 70% of head and neck cancers. Frequent integration into the host genome occurs predominantly in tumorigenic types of HPV. We hypothesize that changes in chromatin state at the location of integration can result in changes in gene expression that contribute to the tumorigenicity of HPV. RESULTS: We find that viral integration events often occur along with changes in chromatin state and expression of genes near the integration site. We investigate whether introduction of new transcription factor binding sites due to HPV integration could invoke these changes. Some regions within the HPV genome, particularly the position of a conserved CTCF binding site, show enriched chromatin accessibility signal. ChIP-seq reveals that the conserved CTCF binding site within the HPV genome binds CTCF in 4 HPV(+) cancer cell lines. Significant changes in CTCF binding pattern and increases in chromatin accessibility occur exclusively within 100 kbp of HPV integration sites. The chromatin changes co-occur with out-sized changes in transcription and alternative splicing of local genes. Analysis of The Cancer Genome Atlas (TCGA) HPV(+) tumors indicates that HPV integration upregulates genes which have significantly higher essentiality scores compared to randomly selected upregulated genes from the same tumors. CONCLUSIONS: Our results suggest that introduction of a new CTCF binding site due to HPV integration reorganizes chromatin state and upregulates genes essential for tumor viability in some HPV(+) tumors. These findings emphasize a newly recognized role of HPV integration in oncogenesis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-023-02926-9. BioMed Central 2023-06-27 /pmc/articles/PMC10294493/ /pubmed/37365652 http://dx.doi.org/10.1186/s13059-023-02926-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Karimzadeh, Mehran Arlidge, Christopher Rostami, Ariana Lupien, Mathieu Bratman, Scott V. Hoffman, Michael M. Human papillomavirus integration transforms chromatin to drive oncogenesis |
title | Human papillomavirus integration transforms chromatin to drive oncogenesis |
title_full | Human papillomavirus integration transforms chromatin to drive oncogenesis |
title_fullStr | Human papillomavirus integration transforms chromatin to drive oncogenesis |
title_full_unstemmed | Human papillomavirus integration transforms chromatin to drive oncogenesis |
title_short | Human papillomavirus integration transforms chromatin to drive oncogenesis |
title_sort | human papillomavirus integration transforms chromatin to drive oncogenesis |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10294493/ https://www.ncbi.nlm.nih.gov/pubmed/37365652 http://dx.doi.org/10.1186/s13059-023-02926-9 |
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