Recurrent integration of human papillomavirus genomes at transcriptional regulatory hubs

Abstract Oncogenic human papillomavirus (HPV) genomes are often integrated into host chromosomes in HPV-associated cancers. HPV genomes are integrated either as a single copy or as tandem repeats of viral DNA interspersed with, or without, host DNA. Integration occurs frequently in common fragile si...

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Autores principales:	Alix Warburton, Tovah E. Markowitz, Joshua P. Katz, James M. Pipas, Alison A. McBride
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/2f2cfc279c734d6eb70f9f70b5b5de01
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spelling	oai:doaj.org-article:2f2cfc279c734d6eb70f9f70b5b5de012021-12-05T12:26:32ZRecurrent integration of human papillomavirus genomes at transcriptional regulatory hubs10.1038/s41525-021-00264-y2056-7944https://doaj.org/article/2f2cfc279c734d6eb70f9f70b5b5de012021-11-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00264-yhttps://doaj.org/toc/2056-7944Abstract Oncogenic human papillomavirus (HPV) genomes are often integrated into host chromosomes in HPV-associated cancers. HPV genomes are integrated either as a single copy or as tandem repeats of viral DNA interspersed with, or without, host DNA. Integration occurs frequently in common fragile sites susceptible to tandem repeat formation and the flanking or interspersed host DNA often contains transcriptional enhancer elements. When co-amplified with the viral genome, these enhancers can form super-enhancer-like elements that drive high viral oncogene expression. Here we compiled highly curated datasets of HPV integration sites in cervical (CESC) and head and neck squamous cell carcinoma (HNSCC) cancers, and assessed the number of breakpoints, viral transcriptional activity, and host genome copy number at each insertion site. Tumors frequently contained multiple distinct HPV integration sites but often only one “driver” site that expressed viral RNA. As common fragile sites and active enhancer elements are cell-type-specific, we mapped these regions in cervical cell lines using FANCD2 and Brd4/H3K27ac ChIP-seq, respectively. Large enhancer clusters, or super-enhancers, were also defined using the Brd4/H3K27ac ChIP-seq dataset. HPV integration breakpoints were enriched at both FANCD2-associated fragile sites and enhancer-rich regions, and frequently showed adjacent focal DNA amplification in CESC samples. We identified recurrent integration “hotspots” that were enriched for super-enhancers, some of which function as regulatory hubs for cell-identity genes. We propose that during persistent infection, extrachromosomal HPV minichromosomes associate with these transcriptional epicenters and accidental integration could promote viral oncogene expression and carcinogenesis.Alix WarburtonTovah E. MarkowitzJoshua P. KatzJames M. PipasAlison A. McBrideNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Alix Warburton Tovah E. Markowitz Joshua P. Katz James M. Pipas Alison A. McBride Recurrent integration of human papillomavirus genomes at transcriptional regulatory hubs
description	Abstract Oncogenic human papillomavirus (HPV) genomes are often integrated into host chromosomes in HPV-associated cancers. HPV genomes are integrated either as a single copy or as tandem repeats of viral DNA interspersed with, or without, host DNA. Integration occurs frequently in common fragile sites susceptible to tandem repeat formation and the flanking or interspersed host DNA often contains transcriptional enhancer elements. When co-amplified with the viral genome, these enhancers can form super-enhancer-like elements that drive high viral oncogene expression. Here we compiled highly curated datasets of HPV integration sites in cervical (CESC) and head and neck squamous cell carcinoma (HNSCC) cancers, and assessed the number of breakpoints, viral transcriptional activity, and host genome copy number at each insertion site. Tumors frequently contained multiple distinct HPV integration sites but often only one “driver” site that expressed viral RNA. As common fragile sites and active enhancer elements are cell-type-specific, we mapped these regions in cervical cell lines using FANCD2 and Brd4/H3K27ac ChIP-seq, respectively. Large enhancer clusters, or super-enhancers, were also defined using the Brd4/H3K27ac ChIP-seq dataset. HPV integration breakpoints were enriched at both FANCD2-associated fragile sites and enhancer-rich regions, and frequently showed adjacent focal DNA amplification in CESC samples. We identified recurrent integration “hotspots” that were enriched for super-enhancers, some of which function as regulatory hubs for cell-identity genes. We propose that during persistent infection, extrachromosomal HPV minichromosomes associate with these transcriptional epicenters and accidental integration could promote viral oncogene expression and carcinogenesis.
format	article
author	Alix Warburton Tovah E. Markowitz Joshua P. Katz James M. Pipas Alison A. McBride
author_facet	Alix Warburton Tovah E. Markowitz Joshua P. Katz James M. Pipas Alison A. McBride
author_sort	Alix Warburton
title	Recurrent integration of human papillomavirus genomes at transcriptional regulatory hubs
title_short	Recurrent integration of human papillomavirus genomes at transcriptional regulatory hubs
title_full	Recurrent integration of human papillomavirus genomes at transcriptional regulatory hubs
title_fullStr	Recurrent integration of human papillomavirus genomes at transcriptional regulatory hubs
title_full_unstemmed	Recurrent integration of human papillomavirus genomes at transcriptional regulatory hubs
title_sort	recurrent integration of human papillomavirus genomes at transcriptional regulatory hubs
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2f2cfc279c734d6eb70f9f70b5b5de01
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Recurrent integration of human papillomavirus genomes at transcriptional regulatory hubs

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