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

Autor: Stephen Smith, Giovanni Bussotti, Cinzia G. Scarpini, Nicholas Coleman, Peter Fraser, Stefan Schoenfelder, Jack M. Monahan, Anton J. Enright, Ian J. Groves, Csilla Várnai, Emma L. A. Drane, Marco Michalski
Přispěvatelé: Groves, Ian J [0000-0001-8882-6701], Michalski, Marco [0000-0002-8470-2338], Monahan, Jack M [0000-0002-0635-0015], Scarpini, Cinzia G [0000-0003-4730-5197], Smith, Stephen P [0000-0001-7744-3238], Várnai, Csilla [0000-0003-0048-9507], Fraser, Peter [0000-0002-0041-1227], Enright, Anton J [0000-0002-6090-3100], Apollo - University of Cambridge Repository, Groves, Ian J. [0000-0001-8882-6701], Monahan, Jack M. [0000-0002-0635-0015], Scarpini, Cinzia G. [0000-0003-4730-5197], Smith, Stephen P. [0000-0001-7744-3238], Enright, Anton J. [0000-0002-6090-3100]
Rok vydání: 2021
Předmět:
Carcinogenesis
Clone (cell biology)
DNA cloning
Gene Expression
Uterine Cervical Neoplasms
Pathology and Laboratory Medicine
Genome
Epigenesis
Genetic
Gene expression
Medicine and Health Sciences
Tumor Cells
Cultured
Biology (General)
Genetics
Viral Genomics
Human papillomavirus 16
Genomics
Chromatin
Medical Microbiology
Viral Pathogens
Viruses
Female
Gene Cloning
Pathogens
Research Article
Papillomaviruses
QH301-705.5
Virus Integration
Immunology
Microbial Genomics
Genome
Viral
Biology
Molecular cloning
Research and Analysis Methods
Microbiology
HPV-16
Virus Effects on Host Gene Expression
Virology
Humans
Epigenetics
Molecular Biology Techniques
Microbial Pathogens
Molecular Biology
Gene
Biology and life sciences
Papillomavirus Infections
Organisms
RC581-607
Parasitology
Immunologic diseases. Allergy
DNA viruses
Cloning
Zdroj: PLoS Pathogens
PLoS Pathogens, Vol 17, Iss 8, p e1009875 (2021)
Popis: 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), 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.
Author summary The integration of human papillomaviruses (HPVs) into host chromosomes is a major feature of HPV-associated cancers, however the process by which this occurs and subsequently drives carcinogenesis is incompletely understood. Here, we devised a state-of-the-art HPV16 genome-specific DNA capture technology to precisely determine the host integration sites at a nucleotide resolution, such that we confirm the mechanism of microhomology-mediated repair (MHMR) during both ‘direct’ and ‘looping’ integration of HPV16 genomes into the host. Furthermore, our technology detects both short- and long-range interactions between HPV16 and host chromatin after virus integration, which correlates with dysregulation of host gene expression at distances up to 500kbp from the integration site. This means that HPV16 genomes can directly affect host gene expression much further away on host chromosomes than initially thought, which may lead to competitive growth advantages for certain integrated clones. Therefore, our study provides further insight into the mechanisms by which papillomaviruses are able to initiate and drive cervical carcinogenesis at an early stage after HPV integration.
Databáze: OpenAIRE
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