Abstract
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.
Highlights
Human papillomavirus (HPV) infection is associated with the development of around 5% of all human cancers, with ~690,000 cases arising annually worldwide[1]
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
As it had previously been shown that interactions between an integrated HPV genome and host chromatin on the same chromosome could lead to changes to host gene expression that could be selected for during carcinogenesis[35], we wished to determine whether these cis interactions were occurring at an earlier stage of cervical neoplasia in our HPV16-positive W12 integrant clones prior to selection
Summary
Human papillomavirus (HPV) infection is associated with the development of around 5% of all human cancers, with ~690,000 cases arising annually worldwide[1]. The integration process usually involves the disruption of the HPV E2 gene and, with loss of this trans-repressive protein product, leads to dysregulation of virus gene expression from the early promoter[5,11,14] Despite this process usually resulting in an increase in HPV oncogene expression associated with cervical SCCs, our previous work has shown that the genomes at initial integration events prior to selection can have levels of expression similar to, or lower than, parental episomal cell lines [15]. This is reflected in the growth rates of these cloned cell lines, which span that of the parental episomal cell line such that an apparent competitive growth advantage is not always evident[15]
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