High-Risk Human Papillomavirus E7 Alters Host DNA Methylome And Represses HLA-E Expression In Human Keratinocytes

Cicchini, L.; Blumhagen, R. Z.; Westrich, J. A.; Meyers, M. E.; Warren, C. J.; Siska, C.; Raben, D.; Kechris, K. J.; Pyeon, D.

doi:10.1101/132902

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bioRxiv · 10.1101/132902

High-Risk Human Papillomavirus E7 Alters Host DNA Methylome And Represses HLA-E Expression In Human Keratinocytes

Cicchini, L.·Blumhagen, R. Z.·Westrich, J. A.·Meyers, M. E.·Warren, C. J.·Siska, C.·Raben, D.·Kechris, K. J.·Pyeon, D.

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Abstract

Human papillomavirus (HPV) infection distinctly alters methylation patterns in HPV-associated cancer. We have recently reported that HPV E7-dependent promoter hypermethylation leads to downregulation of the chemokine CXCL14 and suppression of antitumor immune responses. To investigate the extent of gene expression dysregulated by HPV E7-induced DNA methylation, we analyzed parallel global gene expression and DNA methylation using normal immortalized keratinocyte lines, NIKS, NIKS-16, NIKS-18, and NIKS-16{Delta}E7. We show that expression of the MHC class I genes is downregulated in HPV-positive keratinocytes in an E7-dependent manner. Methylome analysis revealed hypermethylation at a distal CpG island (CGI) near the HLA-E gene in NIKS-16 cells compared to either NIKS cells or NIKS-16{Delta}E7 cells, which lack E7 expression. The HLA-E CGI functions as an active promoter element which is dramatically repressed by DNA methylation. HLA-E protein expression on cell surface is downregulated by high-risk HPV16 and HPV18 E7 expression, but not by low-risk HPV6 and HPV11 E7 expression. Conversely, demethylation at the HLA-E CGI restores HLA-E protein expression in HPV-positive keratinocytes. Because HLA-E plays an important role in antiviral immunity by regulating natural killer and CD8+ T cells, epigenetic downregulation of HLA-E by high-risk HPV E7 may contribute to virus-induced immune evasion during HPV persistence.

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Cicchini, L., Blumhagen, R. Z., Westrich, J. A., Meyers, M. E., Warren, C. J., Siska, C., Raben, D., Kechris, K. J., Pyeon, D.. 2017-05-01. High-Risk Human Papillomavirus E7 Alters Host DNA Methylome And Represses HLA-E Expression In Human Keratinocytes. https://doi.org/10.1101/132902

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