Disruption of CTCF-YY1–dependent looping of the human papillomavirus genome activates differentiation-induced viral oncogene transcription

Pentland, Ieisha, Campos-León, Karen, Cotic, Marius, Davies, Kelli-Jo, Wood, C David, Groves, Ian J, Burley, Megan, Coleman, Nicholas, Stockton, Joanne D, Noyvert, Boris, Beggs, Andrew, West, Michelle J, Roberts, Sally and Parish, Joanna L (2018) Disruption of CTCF-YY1–dependent looping of the human papillomavirus genome activates differentiation-induced viral oncogene transcription. PLoS Biology, 16 (10). e2005752 1-28. ISSN 1544-9173

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Abstract

The complex life cycle of oncogenic human papillomavirus (HPV) initiates in undifferentiated basal epithelial keratinocytes where expression of the E6 and E7 oncogenes is restricted. Upon epithelial differentiation, E6/E7 transcription is increased through unknown mechanisms to drive cellular proliferation required to support virus replication. We report that the chromatin-organising CCCTC-binding factor (CTCF) promotes the formation of a chromatin loop in the HPV genome that epigenetically represses viral enhancer activity controlling E6/E7 expression. CTCF-dependent looping is dependent on the expression of the CTCF-associated Yin Yang 1 (YY1) transcription factor and polycomb repressor complex (PRC) recruitment, resulting in trimethylation of histone H3 at lysine 27. We show that viral oncogene up-regulation during cellular differentiation results from YY1 down-regulation, disruption of viral genome looping, and a loss of epigenetic repression of viral enhancer activity. Our data therefore reveal a key role for CTCF-YY1–dependent looping in the HPV life cycle and identify a regulatory mechanism that could be disrupted in HPV carcinogenesis.

Item Type: Article
Keywords: Virus, oncogene, looping, chromatin, CTCF, cancer
Schools and Departments: School of Life Sciences > Biochemistry
Research Centres and Groups: Gene Expression Research Group
Subjects: Q Science > QR Microbiology > QR0355 Virology
R Medicine > RB Pathology > RB151 Theories of disease. Etiology. Pathogenesis
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology Including cancer and carcinogens > RC0261 Cancer and other malignant neoplasms > RC0268.4 Genetic aspects. Cancer genes
Depositing User: Michelle West
Date Deposited: 01 Nov 2018 12:33
Last Modified: 14 Jan 2019 16:27
URI: http://srodev.sussex.ac.uk/id/eprint/79822

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