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bioRxiv · 10.1101/2020.02.12.942755

Viral integration transforms chromatin to drive oncogenesis

Karimzadeh, M.·Arlidge, C.·Rostami, A.·Lupien, M.·Bratman, S. V.·Hoffman, M. M.
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Abstract

Human papillomavirus (HPV) drives almost all cervical cancers and up to [~]70% of head and neck cancers. Frequent integration into the host genome occurs only for tumourigenic strains of HPV. We hypothesized that changes in the epigenome and transcriptome contribute to the tumourigenicity of HPV. We found that viral integration events often occurred along with changes in chromatin state and expression of genes near the integration site. We investigated whether introduction of new transcription factor binding sites due to HPV integration could invoke these changes. Some regions within the HPV genome, particularly the position of a conserved CTCF binding site, showed enriched chromatin accessibility signal. ChIP-seq revealed that the conserved CTCF binding site within the HPV genome bound CTCF in 4 HPV+ cancer cell lines. Significant changes in CTCF binding pattern and increases in chromatin accessibility occurred exclusively within 100 kbp of HPV integration sites. The chromatin changes co-occurred with out-sized changes in transcription and alternative splicing of local genes. We analyzed the essentiality of genes upregulated around HPV integration sites of The Cancer Genome Atlas (TCGA) HPV+ tumours. HPV integration upregulated genes which had significantly higher essentiality scores compared to randomly selected upregulated genes from the same tumours. Our results suggest that introduction of a new CTCF binding site due to HPV integration reorganizes chromatin and upregulates genes essential for tumour viability in some HPV+ tumours. These findings emphasize a newly recognized role of HPV integration in oncogenesis.

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Karimzadeh, M., Arlidge, C., Rostami, A., Lupien, M., Bratman, S. V., Hoffman, M. M.. 2020-02-13. Viral integration transforms chromatin to drive oncogenesis. https://doi.org/10.1101/2020.02.12.942755

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