Journal
JOURNAL OF VIROLOGY
Volume 89, Issue 9, Pages 4770-4785Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.00097-15
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Funding
- University of St. Andrews, School of Medicine
- Cancer Research UK (CRUK)
- CRUK [13080]
- Royal Society University Research Fellowship [UF110010]
- Cancer Research UK [13080] Funding Source: researchfish
- Royal Society [UF110010] Funding Source: Royal Society
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Host cell differentiation-dependent regulation of human papillomavirus (HPV) gene expression is required for productive infection. The host cell CCCTC-binding factor (CTCF) functions in genome-wide chromatin organization and gene regulation. We have identified a conserved CTCF binding site in the E2 open reading frame of high-risk HPV types. Using organotypic raft cultures of primary human keratinocytes containing high-risk HPV18 genomes, we show that CTCF recruitment to this conserved site regulates viral gene expression in differentiating epithelia. Mutation of the CTCF binding site increases the expression of the viral oncoproteins E6 and E7 and promotes host cell proliferation. Loss of CTCF binding results in a reduction of a specific alternatively spliced transcript expressed from the early gene region concomitant with an increase in the abundance of unspliced early transcripts. We conclude that high-risk HPV types have evolved to recruit CTCF to the early gene region to control the balance and complexity of splicing events that regulate viral oncoprotein expression.
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