In FY 2018, we investigated how HPV integration could result in de novo super-enhancer formation in cervical cancer. We characterized the chromatin and genomic landscape of a super-enhancer associated HPV integration site using whole genome sequencing, RNAseq, ChIPseq and molecular combing/fiber-FISH. We showed that 26 copies of HPV16 are integrated into an intergenic region of the human genome, interspersed with 25 kb of amplified, flanking cellular DNA. This interspersed, co-amplified viral-host pattern is frequent in HPV-associated cancers. An abundant viral-cellular fusion transcript encoding the viral E6/E7 oncogenes is expressed from the integration locus and the chromatin encompassing the viral enhancer and a region in the adjacent amplified cellular sequences is strongly enriched in super-enhancer markers, H3K27ac and Brd4. Notably, the peak in the amplified cellular sequence corresponds to an epithelial-cell-type specific enhancer. Thus, HPV16 integration generated a super-enhancer-like element composed of tandem interspersed copies of the viral upstream regulatory region and a cellular enhancer. The genetic and epigenetic signature of this locus promoted the formation of the super-enhancer to drive high viral oncogene expression. This provides insight into the genesis of super-enhancers and is a novel mechanism by which HPV integration can promote oncogenesis. Targeted disruption of factors binding to this element decreases viral transcription and causes cell death. Thus, cancer cells harboring integrated HPV may be targeted by therapeutics that disrupt super-enhancer function.
| McBride, Alison A; Münger, Karl (2018) Expert Views on HPV Infection. Viruses 10: |
| Warburton, Alix; Redmond, Catherine J; Dooley, Katharine E et al. (2018) HPV integration hijacks and multimerizes a cellular enhancer to generate a viral-cellular super-enhancer that drives high viral oncogene expression. PLoS Genet 14:e1007179 |
| McBride, Alison A (2017) Oncogenic human papillomaviruses. Philos Trans R Soc Lond B Biol Sci 372: |
| McBride, Alison A (2017) Playing with fire: consequences of human papillomavirus DNA replication adjacent to genetically unstable regions of host chromatin. Curr Opin Virol 26:63-68 |
| McBride, Alison A; Warburton, Alix (2017) The role of integration in oncogenic progression of HPV-associated cancers. PLoS Pathog 13:e1006211 |
| Dooley, Katharine E; Warburton, Alix; McBride, Alison A (2016) Tandemly Integrated HPV16 Can Form a Brd4-Dependent Super-Enhancer-Like Element That Drives Transcription of Viral Oncogenes. MBio 7: |
