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Article: EBV infection is associated with histone bivalent switch modifications in squamous epithelial cells

TitleEBV infection is associated with histone bivalent switch modifications in squamous epithelial cells
Authors
KeywordsEpstein−Barr virus
histone bivalent switch
DNA methylation
DNA damage repair pathway
MLH1
Issue Date2019
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings of the National Academy of Sciences, 2019, v. 116 n. 28, p. 14144-14153 How to Cite?
AbstractEpstein−Barr virus (EBV) induces histone modifications to regulate signaling pathways involved in EBV-driven tumorigenesis. To date, the regulatory mechanisms involved are poorly understood. In this study, we show that EBV infection of epithelial cells is associated with aberrant histone modification; specifically, aberrant histone bivalent switches by reducing the transcriptional activation histone mark (H3K4me3) and enhancing the suppressive mark (H3K27me3) at the promoter regions of a panel of DNA damage repair members in immortalized nasopharyngeal epithelial (NPE) cells. Sixteen DNA damage repair family members in base excision repair (BER), homologous recombination, nonhomologous end-joining, and mismatch repair (MMR) pathways showed aberrant histone bivalent switches. Among this panel of DNA repair members, MLH1, involved in MMR, was significantly down-regulated in EBV-infected NPE cells through aberrant histone bivalent switches in a promoter hypermethylation-independent manner. Functionally, expression of MLH1 correlated closely with cisplatin sensitivity both in vitro and in vivo. Moreover, seven BER members with aberrant histone bivalent switches in the EBV-positive NPE cell lines were significantly enriched in pathway analysis in a promoter hypermethylation-independent manner. This observation is further validated by their down-regulation in EBV-infected NPE cells. The in vitro comet and apurinic/apyrimidinic site assays further confirmed that EBV-infected NPE cells showed reduced DNA damage repair responsiveness. These findings suggest the importance of EBV-associated aberrant histone bivalent switch in host cells in subsequent suppression of DNA damage repair genes in a methylation-independent manner.
Persistent Identifierhttp://hdl.handle.net/10722/272155
ISSN
2019 Impact Factor: 9.412
2015 SCImago Journal Rankings: 6.883
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLeong, ML-
dc.contributor.authorCheung, AKL-
dc.contributor.authorDai, W-
dc.contributor.authorTsao, GSW-
dc.contributor.authorTsang, CM-
dc.contributor.authorDawson, CW-
dc.contributor.authorKo, JMY-
dc.contributor.authorLung, ML-
dc.date.accessioned2019-07-20T10:36:45Z-
dc.date.available2019-07-20T10:36:45Z-
dc.date.issued2019-
dc.identifier.citationProceedings of the National Academy of Sciences, 2019, v. 116 n. 28, p. 14144-14153-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/272155-
dc.description.abstractEpstein−Barr virus (EBV) induces histone modifications to regulate signaling pathways involved in EBV-driven tumorigenesis. To date, the regulatory mechanisms involved are poorly understood. In this study, we show that EBV infection of epithelial cells is associated with aberrant histone modification; specifically, aberrant histone bivalent switches by reducing the transcriptional activation histone mark (H3K4me3) and enhancing the suppressive mark (H3K27me3) at the promoter regions of a panel of DNA damage repair members in immortalized nasopharyngeal epithelial (NPE) cells. Sixteen DNA damage repair family members in base excision repair (BER), homologous recombination, nonhomologous end-joining, and mismatch repair (MMR) pathways showed aberrant histone bivalent switches. Among this panel of DNA repair members, MLH1, involved in MMR, was significantly down-regulated in EBV-infected NPE cells through aberrant histone bivalent switches in a promoter hypermethylation-independent manner. Functionally, expression of MLH1 correlated closely with cisplatin sensitivity both in vitro and in vivo. Moreover, seven BER members with aberrant histone bivalent switches in the EBV-positive NPE cell lines were significantly enriched in pathway analysis in a promoter hypermethylation-independent manner. This observation is further validated by their down-regulation in EBV-infected NPE cells. The in vitro comet and apurinic/apyrimidinic site assays further confirmed that EBV-infected NPE cells showed reduced DNA damage repair responsiveness. These findings suggest the importance of EBV-associated aberrant histone bivalent switch in host cells in subsequent suppression of DNA damage repair genes in a methylation-independent manner.-
dc.languageeng-
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org-
dc.relation.ispartofProceedings of the National Academy of Sciences-
dc.rightsProceedings of the National Academy of Sciences. Copyright © National Academy of Sciences.-
dc.subjectEpstein−Barr virus-
dc.subjecthistone bivalent switch-
dc.subjectDNA methylation-
dc.subjectDNA damage repair pathway-
dc.subjectMLH1-
dc.titleEBV infection is associated with histone bivalent switch modifications in squamous epithelial cells-
dc.typeArticle-
dc.identifier.emailLeong, ML: merrin@hku.hk-
dc.identifier.emailCheung, AKL: arthurhk@hku.hk-
dc.identifier.emailDai, W: weidai2@hku.hk-
dc.identifier.emailTsao, GSW: gswtsao@hku.hk-
dc.identifier.emailKo, JMY: joko@hku.hk-
dc.identifier.emailLung, ML: mlilung@hku.hk-
dc.identifier.authorityCheung, AKL=rp01769-
dc.identifier.authorityDai, W=rp02146-
dc.identifier.authorityTsao, GSW=rp00399-
dc.identifier.authorityKo, JMY=rp02011-
dc.identifier.authorityLung, ML=rp00300-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.1821752116-
dc.identifier.pmid31235597-
dc.identifier.pmcidPMC6628793-
dc.identifier.scopuseid_2-s2.0-85068551244-
dc.identifier.hkuros299032-
dc.identifier.hkuros302870-
dc.identifier.volume116-
dc.identifier.issue28-
dc.identifier.spage14144-
dc.identifier.epage14153-
dc.identifier.isiWOS:000474535700070-
dc.publisher.placeUnited States-

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