HPV integration hijacks and multimerizes a cellular enhancer to generate a viral-cellular super-enhancer that drives high viral oncogene expression

Alix Warburton, Catherine J. Redmond, Katharine E. Dooley, Haiqing Fu, Maura L. Gillison, Keiko Akagi, David E. Symer, Mirit I. Aladjem, Alison A. McBride

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Integration of human papillomavirus (HPV) genomes into cellular chromatin is common in HPV-associated cancers. Integration is random, and each site is unique depending on how and where the virus integrates. We recently showed that tandemly integrated HPV16 could result in the formation of a super-enhancer-like element that drives transcription of the viral oncogenes. Here, we characterize the chromatin landscape and genomic architecture of this integration locus to elucidate the mechanisms that promoted de novo super-enhancer formation. Using next-generation sequencing and molecular combing/fiber-FISH, we show that ~26 copies of HPV16 are integrated into an intergenic region of chromosome 2p23.2, interspersed with 25 kb of amplified, flanking cellular DNA. This interspersed, co-amplified viral-host pattern is frequent in HPV-associated cancers and here we designate it as Type III integration. An abundant viral-cellular fusion transcript encoding the viral E6/E7 oncogenes is expressed from the integration locus and the chromatin encompassing both the viral enhancer and a region in the adjacent amplified cellular sequences is strongly enriched in the 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, to drive high levels of oncogene expression.

Original languageEnglish (US)
Article numbere1007179
JournalPLoS genetics
Volume14
Issue number1
DOIs
StatePublished - Jan 2018

Fingerprint

Papillomaviridae
oncogenes
Oncogenes
Chromatin
chromatin
cancer
chromosome
genomics
virus
loci
Intergenic DNA
neoplasms
genome
Nucleic Acid Regulatory Sequences
Human Genome
intergenic DNA
DNA
Neoplasms
epithelial cells
transcription (genetics)

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

HPV integration hijacks and multimerizes a cellular enhancer to generate a viral-cellular super-enhancer that drives high viral oncogene expression. / Warburton, Alix; Redmond, Catherine J.; Dooley, Katharine E.; Fu, Haiqing; Gillison, Maura L.; Akagi, Keiko; Symer, David E.; Aladjem, Mirit I.; McBride, Alison A.

In: PLoS genetics, Vol. 14, No. 1, e1007179, 01.2018.

Research output: Contribution to journalArticle

Warburton, Alix ; Redmond, Catherine J. ; Dooley, Katharine E. ; Fu, Haiqing ; Gillison, Maura L. ; Akagi, Keiko ; Symer, David E. ; Aladjem, Mirit I. ; McBride, Alison A. / HPV integration hijacks and multimerizes a cellular enhancer to generate a viral-cellular super-enhancer that drives high viral oncogene expression. In: PLoS genetics. 2018 ; Vol. 14, No. 1.
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