Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis.
Drane, Emma LA
Public Library of Science (PLoS)
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Groves, I. J., Drane, E. L., Michalski, M., Monahan, J. M., Scarpini, C. G., Smith, S. P., Bussotti, G., et al. (2021). Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis.. PLoS Pathog, 17 (8), e1009875. https://doi.org/10.1371/journal.ppat.1009875
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.
This work was supported by Cancer Research UK (www.cancerresearchuk.org) Programme Award (A13080) to NC. ELAD was supported by a PhD studentship from The Pathological Society of GB & NI (www.pathsoc. org) awarded to IJG and NC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Cancer Research Uk (None)
External DOI: https://doi.org/10.1371/journal.ppat.1009875
This record's URL: https://www.repository.cam.ac.uk/handle/1810/329938
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/