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 panel c to Figure 1, showing an example of the extent of CTCF binding in the HPV genome compared to the neighbouring host genomic region at the integration site. Added investigation of whether the direction of chimeric HPV affects the magnitude of changes in neighboring genomic regions. Fixed error in referring to direction of chimeric transcripts. Added citations to more previous work and recent work investigating transcriptome and epigenome changes upon HPV integration and clarified what is still not known.
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE143026