Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis.

Development of cervical cancer is directly associated with integration of human papillomavirus (HPV) genomes into host chromosomes and subsequent modulation of HPV oncogene expression, which correlates with multi-layered epigenetic changes at the integrated HPV genomes. However, the process of integ...

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Autores principales:	Ian J Groves, Emma L A Drane, Marco Michalski, Jack M Monahan, Cinzia G Scarpini, Stephen P Smith, Giovanni Bussotti, Csilla Várnai, Stefan Schoenfelder, Peter Fraser, Anton J Enright, Nicholas Coleman
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/c2ebaa15d87542a8b9191e3a5a74e587
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spelling	oai:doaj.org-article:c2ebaa15d87542a8b9191e3a5a74e5872021-12-02T20:00:15ZShort- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis.1553-73661553-737410.1371/journal.ppat.1009875https://doaj.org/article/c2ebaa15d87542a8b9191e3a5a74e5872021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009875https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Development of cervical cancer is directly associated with integration of human papillomavirus (HPV) genomes into host chromosomes and subsequent modulation of HPV oncogene expression, which correlates with multi-layered epigenetic changes at the integrated HPV genomes. However, the process of integration itself and dysregulation of host gene expression at sites of integration in our model of HPV16 integrant clone natural selection has remained enigmatic. We now show, using a state-of-the-art 'HPV integrated site capture' (HISC) technique, that integration likely occurs through microhomology-mediated repair (MHMR) mechanisms via either a direct process, resulting in host sequence deletion (in our case, partially homozygously) or via a 'looping' mechanism by which flanking host regions become amplified. Furthermore, using our 'HPV16-specific Region Capture Hi-C' technique, we have determined that chromatin interactions between the integrated virus genome and host chromosomes, both at short- (<500 kbp) and long-range (>500 kbp), appear to drive local host gene dysregulation through the disruption of host:host interactions within (but not exceeding) host structures known as topologically associating domains (TADs). This mechanism of HPV-induced host gene expression modulation indicates that integration of virus genomes near to or within a 'cancer-causing gene' is not essential to influence their expression and that these modifications to genome interactions could have a major role in selection of HPV integrants at the early stage of cervical neoplastic progression.Ian J GrovesEmma L A DraneMarco MichalskiJack M MonahanCinzia G ScarpiniStephen P SmithGiovanni BussottiCsilla VárnaiStefan SchoenfelderPeter FraserAnton J EnrightNicholas ColemanPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 8, p e1009875 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Ian J Groves Emma L A Drane Marco Michalski Jack M Monahan Cinzia G Scarpini Stephen P Smith Giovanni Bussotti Csilla Várnai Stefan Schoenfelder Peter Fraser Anton J Enright Nicholas Coleman Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis.
description	Development of cervical cancer is directly associated with integration of human papillomavirus (HPV) genomes into host chromosomes and subsequent modulation of HPV oncogene expression, which correlates with multi-layered epigenetic changes at the integrated HPV genomes. However, the process of integration itself and dysregulation of host gene expression at sites of integration in our model of HPV16 integrant clone natural selection has remained enigmatic. We now show, using a state-of-the-art 'HPV integrated site capture' (HISC) technique, that integration likely occurs through microhomology-mediated repair (MHMR) mechanisms via either a direct process, resulting in host sequence deletion (in our case, partially homozygously) or via a 'looping' mechanism by which flanking host regions become amplified. Furthermore, using our 'HPV16-specific Region Capture Hi-C' technique, we have determined that chromatin interactions between the integrated virus genome and host chromosomes, both at short- (<500 kbp) and long-range (>500 kbp), appear to drive local host gene dysregulation through the disruption of host:host interactions within (but not exceeding) host structures known as topologically associating domains (TADs). This mechanism of HPV-induced host gene expression modulation indicates that integration of virus genomes near to or within a 'cancer-causing gene' is not essential to influence their expression and that these modifications to genome interactions could have a major role in selection of HPV integrants at the early stage of cervical neoplastic progression.
format	article
author	Ian J Groves Emma L A Drane Marco Michalski Jack M Monahan Cinzia G Scarpini Stephen P Smith Giovanni Bussotti Csilla Várnai Stefan Schoenfelder Peter Fraser Anton J Enright Nicholas Coleman
author_facet	Ian J Groves Emma L A Drane Marco Michalski Jack M Monahan Cinzia G Scarpini Stephen P Smith Giovanni Bussotti Csilla Várnai Stefan Schoenfelder Peter Fraser Anton J Enright Nicholas Coleman
author_sort	Ian J Groves
title	Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis.
title_short	Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis.
title_full	Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis.
title_fullStr	Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis.
title_full_unstemmed	Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis.
title_sort	short- and long-range cis interactions between integrated hpv genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/c2ebaa15d87542a8b9191e3a5a74e587
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Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis.

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