Cis‐regulatory effect of HPV integration is constrained by host chromatin architecture in cervical cancers

Abstract

Human papillomavirus (HPV) infections are the primary drivers of cervical cancers, and often HPV DNA gets integrated into the host genome. Although the oncogenic impact of HPV encoded genes is relatively well known, the cis‐regulatory effect of integrated HPV DNA on host chromatin structure and gene regulation remains less understood. We investigated genome‐wide patterns of HPV integrations and associated host gene expression changes in the context of host chromatin states and topologically associating domains (TADs). HPV integrations were significantly enriched in active chromatin regions and depleted in inactive ones. Interestingly, regardless of chromatin state, genomic regions flanking HPV integrations showed transcriptional upregulation. Nevertheless, upregulation (both local and long‐range) was mostly confined to TADs with integration, but not affecting adjacent TADs. Few TADs showed recurrent integrations associated with overexpression of oncogenes within them (e.g. MYC, PVT1, TP63 and ERBB2) regardless of proximity. Hi‐C and 4C‐seq analyses in cervical cancer cell line (HeLa) demonstrated chromatin looping interactions between integrated HPV and MYC/PVT1 regions (~ 500 kb apart), leading to allele‐specific overexpression. Based on these, we propose HPV integrations can trigger multimodal oncogenic activation to promote cancer progression.

Decoding HPV: disease stage and treatment insights

“…In the current issue of Molecular Oncology, Singh et al [4] focused on HPV integration into the host genome and investigated cis-regulatory effect on chromatin and gene regulation. Using genome-wide DNA-based approaches, the authors analysed HPV integration locations in the host genome of patients with cervical cancer.…”

“…An outlook of HPV in oncogenesis and its role in therapy. The integrated HPV DNA can induce transcriptional upregulation in vicinity or transcription of oncogenes through long-range chromatin interactions [4] and the level of ccfHPV DNA is related to disease severity [7]. In addition, plasma IL-8/IL-18 levels can be used as biomarkers for predicting therapy response in HPV-related cancers [8].…”