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Viral integration transforms chromatin to drive oncogenesis

View ORCID ProfileMehran Karimzadeh, View ORCID ProfileChristopher Arlidge, View ORCID ProfileAriana Rostami, View ORCID ProfileMathieu Lupien, View ORCID ProfileScott V. Bratman, View ORCID ProfileMichael M. Hoffman
doi: https://doi.org/10.1101/2020.02.12.942755
Mehran Karimzadeh
1Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
2Princess Margaret Cancer Centre, Toronto, ON, Canada
3Vector Institute, Toronto, ON, Canada
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  • ORCID record for Mehran Karimzadeh
Christopher Arlidge
2Princess Margaret Cancer Centre, Toronto, ON, Canada
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Ariana Rostami
1Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
2Princess Margaret Cancer Centre, Toronto, ON, Canada
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Mathieu Lupien
1Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
2Princess Margaret Cancer Centre, Toronto, ON, Canada
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  • ORCID record for Mathieu Lupien
Scott V. Bratman
1Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
2Princess Margaret Cancer Centre, Toronto, ON, Canada
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Michael M. Hoffman
1Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
2Princess Margaret Cancer Centre, Toronto, ON, Canada
3Vector Institute, Toronto, ON, Canada
4Department of Computer Science, University of Toronto, Toronto, ON, Canada
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  • ORCID record for Michael M. Hoffman
  • For correspondence: michael.hoffman@utoronto.ca
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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 sequence motif, showed enriched chromatin accessibility signal. ChIP-seq revealed that the conserved CTCF sequence motif within the HPV genome bound CTCF in 5 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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵5 Lead contact: michael.hoffman{at}utoronto.ca, scott.bratman{at}rmp.uhn.ca, mathieu.lupien{at}uhnresearch.ca

  • Added author contributions; Fixed capitalization in the Supplementary Table Data Dictionary.

  • https://github.com/hoffmangroup/polyidus

  • https://doi.org/10.5281/zenodo.3780203

  • https://doi.org/10.5281/zenodo.3780364

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE143026

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 03, 2020.
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Viral integration transforms chromatin to drive oncogenesis
Mehran Karimzadeh, Christopher Arlidge, Ariana Rostami, Mathieu Lupien, Scott V. Bratman, Michael M. Hoffman
bioRxiv 2020.02.12.942755; doi: https://doi.org/10.1101/2020.02.12.942755
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Viral integration transforms chromatin to drive oncogenesis
Mehran Karimzadeh, Christopher Arlidge, Ariana Rostami, Mathieu Lupien, Scott V. Bratman, Michael M. Hoffman
bioRxiv 2020.02.12.942755; doi: https://doi.org/10.1101/2020.02.12.942755

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