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Epigenetic and transcriptional changes which follow Epstein-Barr virus infection of germinal center B cells and their relevance to the pathogenesis of Hodgkin's lymphoma.
J Virol 2011; 85(18):9568-77JV

Abstract

Although Epstein-Barr virus (EBV) usually establishes an asymptomatic lifelong infection, it is also implicated in the development of germinal center (GC) B-cell-derived malignancies, including Hodgkin's lymphoma (HL). Following primary infection, EBV remains latent in the memory B-cell population, where host-driven methylation of viral DNA contributes to the repression of viral gene expression. However, it is still unclear how EBV harnesses the cell's methylation machinery in B cells, how this contributes to viral persistence, and what impact this has on the methylation of cellular genes. We show that EBV infection of GC B cells is followed by upregulation of the DNA methyltransferase DNMT3A and downregulation of DNMT3B and DNMT1. We show that the EBV latent membrane protein 1 (LMP1) oncogene downregulates DNMT1 and that DNMT3A binds to the viral promoter Wp. Genome-wide promoter arrays performed with these cells showed that EBV-associated methylation changes in cellular genes were not randomly distributed across the genome but clustered at chromosomal locations, consistent with an instructive pattern of methylation, and were in part determined by promoter CpG content. Both DNMT3B and DNMT1 were downregulated and DNMT3A was upregulated in HL cell lines, recapitulating the pattern of expression observed following EBV infection of GC B cells. We also found, by using gene expression profiling, that genes differentially expressed following EBV infection of GC B cells were significantly enriched for those reported to be differentially expressed in HL. These observations suggest that EBV-infected GC B cells are a useful model for studying virus-associated changes contributing to the pathogenesis of HL.

Authors+Show Affiliations

College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK B15 2TT, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21752916

Citation

Leonard, Sarah, et al. "Epigenetic and Transcriptional Changes Which Follow Epstein-Barr Virus Infection of Germinal Center B Cells and Their Relevance to the Pathogenesis of Hodgkin's Lymphoma." Journal of Virology, vol. 85, no. 18, 2011, pp. 9568-77.
Leonard S, Wei W, Anderton J, et al. Epigenetic and transcriptional changes which follow Epstein-Barr virus infection of germinal center B cells and their relevance to the pathogenesis of Hodgkin's lymphoma. J Virol. 2011;85(18):9568-77.
Leonard, S., Wei, W., Anderton, J., Vockerodt, M., Rowe, M., Murray, P. G., & Woodman, C. B. (2011). Epigenetic and transcriptional changes which follow Epstein-Barr virus infection of germinal center B cells and their relevance to the pathogenesis of Hodgkin's lymphoma. Journal of Virology, 85(18), pp. 9568-77. doi:10.1128/JVI.00468-11.
Leonard S, et al. Epigenetic and Transcriptional Changes Which Follow Epstein-Barr Virus Infection of Germinal Center B Cells and Their Relevance to the Pathogenesis of Hodgkin's Lymphoma. J Virol. 2011;85(18):9568-77. PubMed PMID: 21752916.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Epigenetic and transcriptional changes which follow Epstein-Barr virus infection of germinal center B cells and their relevance to the pathogenesis of Hodgkin's lymphoma. AU - Leonard,Sarah, AU - Wei,Wenbin, AU - Anderton,Jennifer, AU - Vockerodt,Martina, AU - Rowe,Martin, AU - Murray,Paul G, AU - Woodman,Ciaran B, Y1 - 2011/07/13/ PY - 2011/7/15/entrez PY - 2011/7/15/pubmed PY - 2011/10/12/medline SP - 9568 EP - 77 JF - Journal of virology JO - J. Virol. VL - 85 IS - 18 N2 - Although Epstein-Barr virus (EBV) usually establishes an asymptomatic lifelong infection, it is also implicated in the development of germinal center (GC) B-cell-derived malignancies, including Hodgkin's lymphoma (HL). Following primary infection, EBV remains latent in the memory B-cell population, where host-driven methylation of viral DNA contributes to the repression of viral gene expression. However, it is still unclear how EBV harnesses the cell's methylation machinery in B cells, how this contributes to viral persistence, and what impact this has on the methylation of cellular genes. We show that EBV infection of GC B cells is followed by upregulation of the DNA methyltransferase DNMT3A and downregulation of DNMT3B and DNMT1. We show that the EBV latent membrane protein 1 (LMP1) oncogene downregulates DNMT1 and that DNMT3A binds to the viral promoter Wp. Genome-wide promoter arrays performed with these cells showed that EBV-associated methylation changes in cellular genes were not randomly distributed across the genome but clustered at chromosomal locations, consistent with an instructive pattern of methylation, and were in part determined by promoter CpG content. Both DNMT3B and DNMT1 were downregulated and DNMT3A was upregulated in HL cell lines, recapitulating the pattern of expression observed following EBV infection of GC B cells. We also found, by using gene expression profiling, that genes differentially expressed following EBV infection of GC B cells were significantly enriched for those reported to be differentially expressed in HL. These observations suggest that EBV-infected GC B cells are a useful model for studying virus-associated changes contributing to the pathogenesis of HL. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/21752916/Epigenetic_and_transcriptional_changes_which_follow_Epstein_Barr_virus_infection_of_germinal_center_B_cells_and_their_relevance_to_the_pathogenesis_of_Hodgkin's_lymphoma_ L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=21752916 DB - PRIME DP - Unbound Medicine ER -