1. EBV infection is associated with histone bivalent switch modifications in squamous epithelial cells.
- Author
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Leong MML, Cheung AKL, Dai W, Tsao SW, Tsang CM, Dawson CW, Mun Yee Ko J, and Lung ML
- Subjects
- CpG Islands genetics, DNA Damage genetics, DNA Methylation genetics, DNA Mismatch Repair genetics, DNA Repair genetics, Epithelial Cells metabolism, Epithelial Cells virology, Epstein-Barr Virus Infections pathology, Epstein-Barr Virus Infections virology, Gene Expression Regulation genetics, Herpesvirus 4, Human pathogenicity, Homologous Recombination genetics, Humans, MutL Protein Homolog 1 genetics, Nasopharynx growth & development, Nasopharynx pathology, Nasopharynx virology, Promoter Regions, Genetic, Epstein-Barr Virus Infections genetics, Herpesvirus 4, Human genetics, Histone Code genetics, Histones genetics
- Abstract
Epstein-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., Competing Interests: The authors declare no conflict of interest.
- Published
- 2019
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