Warburton Alix, Markowitz Tovah E, Miranda Jj L, Majumder Kinjal, McBride Alison A
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, 33 North Drive, MSC3209, National Institutes of Health, Bethesda, Maryland 20892, USA.
Integrated Data Sciences Section, Research Technologies Branch, NIAID, NIH, Bethesda, Maryland, USA.
bioRxiv. 2025 Apr 17:2025.04.15.649012. doi: 10.1101/2025.04.15.649012.
Human papillomaviruses (HPVs) maintain their genomes as minichromosomes in the nuclei of infected keratinocytes. This study investigates the association of HPV31 genomes with host chromatin using both HiC and 4C-seq chromosome conformation capture techniques. We show that HPV31 genomes preferentially associate with transcriptionally active A compartments of host chromatin, regions of open chromatin defined by ATAC-seq, and super-enhancers defined by Brd4 and H3K27ac ChIP-seq. The viral genome association sites were also highly correlated with genomic loci previously identified as common HPV integration sites in cervical cancers. Recent studies have shown that transcriptionally active sites are prone to dsDNA breaks, and we find a strong correlation among dsBREAK datasets with transcriptionally active and open regions of host chromatin and the HPV31 genome association sites defined in our study. These findings suggest that HPV genomes associate with cellular transcriptional epicenters to maintain active viral gene expression during persistent infection, but also indicate that the susceptibility of these regions to dsDNA breaks could explain their propensity for viral DNA integration in HPV-associated cancers.
人乳头瘤病毒（HPV）在受感染角质形成细胞的细胞核中以微型染色体的形式维持其基因组。本研究使用HiC和4C-seq染色体构象捕获技术研究HPV31基因组与宿主染色质的关联。我们发现，HPV31基因组优先与宿主染色质的转录活跃A区室、由ATAC-seq定义的开放染色质区域以及由Brd4和H3K27ac ChIP-seq定义的超级增强子相关联。病毒基因组关联位点也与先前在宫颈癌中鉴定为常见HPV整合位点的基因组位点高度相关。最近的研究表明，转录活跃位点容易发生双链DNA断裂，并且我们发现双链断裂数据集与宿主染色质的转录活跃和开放区域以及我们研究中定义的HPV31基因组关联位点之间存在很强的相关性。这些发现表明，HPV基因组与细胞转录中心相关联，以在持续感染期间维持活跃的病毒基因表达，但也表明这些区域对双链DNA断裂的敏感性可以解释它们在HPV相关癌症中病毒DNA整合的倾向。
