High-Risk Human Papillomavirus E7 Alters Host DNA Methylome and Represses HLA-E Expression in Human Keratinocytes
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 e...
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| Format: | Article |
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Nature Portfolio
2017-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-03295-7 |
| _version_ | 1829464494820032512 |
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| author | Louis Cicchini Rachel Z. Blumhagen Joseph A. Westrich Mallory E. Myers Cody J. Warren Charlotte Siska David Raben Katerina J. Kechris Dohun Pyeon |
| author_facet | Louis Cicchini Rachel Z. Blumhagen Joseph A. Westrich Mallory E. Myers Cody J. Warren Charlotte Siska David Raben Katerina J. Kechris Dohun Pyeon |
| author_sort | Louis Cicchini |
| collection | DOAJ |
| description | 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∆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∆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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| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-13T16:37:19Z |
| publishDate | 2017-06-01 |
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| series | Scientific Reports |
| spelling | doaj.art-b1daac7ff6fd46fa8f98a8fd822bbdf32022-12-21T23:38:21ZengNature PortfolioScientific Reports2045-23222017-06-017111310.1038/s41598-017-03295-7High-Risk Human Papillomavirus E7 Alters Host DNA Methylome and Represses HLA-E Expression in Human KeratinocytesLouis Cicchini0Rachel Z. Blumhagen1Joseph A. Westrich2Mallory E. Myers3Cody J. Warren4Charlotte Siska5David Raben6Katerina J. Kechris7Dohun Pyeon8Department of Immunology and Microbiology, University of Colorado School of MedicineDepartment of Biostatistics and Informatics, Colorado School of Public HealthDepartment of Immunology and Microbiology, University of Colorado School of MedicineDepartment of Immunology and Microbiology, University of Colorado School of MedicineDepartment of Immunology and Microbiology, University of Colorado School of MedicineDepartment of Biostatistics and Informatics, Colorado School of Public HealthDepartment of Radiation Oncology, University of Colorado School of MedicineDepartment of Biostatistics and Informatics, Colorado School of Public HealthDepartment of Immunology and Microbiology, University of Colorado School of MedicineAbstract 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∆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∆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.https://doi.org/10.1038/s41598-017-03295-7 |
| spellingShingle | Louis Cicchini Rachel Z. Blumhagen Joseph A. Westrich Mallory E. Myers Cody J. Warren Charlotte Siska David Raben Katerina J. Kechris Dohun Pyeon High-Risk Human Papillomavirus E7 Alters Host DNA Methylome and Represses HLA-E Expression in Human Keratinocytes Scientific Reports |
| title | High-Risk Human Papillomavirus E7 Alters Host DNA Methylome and Represses HLA-E Expression in Human Keratinocytes |
| title_full | High-Risk Human Papillomavirus E7 Alters Host DNA Methylome and Represses HLA-E Expression in Human Keratinocytes |
| title_fullStr | High-Risk Human Papillomavirus E7 Alters Host DNA Methylome and Represses HLA-E Expression in Human Keratinocytes |
| title_full_unstemmed | High-Risk Human Papillomavirus E7 Alters Host DNA Methylome and Represses HLA-E Expression in Human Keratinocytes |
| title_short | High-Risk Human Papillomavirus E7 Alters Host DNA Methylome and Represses HLA-E Expression in Human Keratinocytes |
| title_sort | high risk human papillomavirus e7 alters host dna methylome and represses hla e expression in human keratinocytes |
| url | https://doi.org/10.1038/s41598-017-03295-7 |
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