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dc.contributor.authorPaschos, Ken_US
dc.contributor.authorSmith, Pen_US
dc.contributor.authorAnderton, Een_US
dc.contributor.authorMiddeldorp, JMen_US
dc.contributor.authorWhite, REen_US
dc.contributor.authorAllday, MJen_US
dc.date.accessioned2018-08-29T13:04:25Z
dc.date.issued2009-06en_US
dc.identifier6en_US
dc.identifier.citationPLOS PATHOGENS, 2009, 5en_US
dc.identifier.issn1553-7366en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2408
dc.identifier.eissn1553-7374en_US
dc.identifier.doi10.1371/journal.ppat.1000492en_US
dc.description.abstractIn human B cells infected with Epstein-Barr virus (EBV), latency-associated virus gene products inhibit expression of the proapoptotic Bcl-2-family member Bim and enhance cell survival. This involves the activities of the EBV nuclear proteins EBNA3A and EBNA3C and appears to be predominantly directed at regulating Bim mRNA synthesis, although post-transcriptional regulation of Bim has been reported. Here we show that protein and RNA stability make little or no contribution to the EBV-associated repression of Bim in latently infected B cells. However, treatment of cells with inhibitors of histone deacetylase (HDAC) and DNA methyltransferase (DNMT) enzymes indicated that epigenetic mechanisms are involved in the down-regulation of Bim. This was initially confirmed by chromatin immunoprecipitation analysis of histone acetylation levels on the Bim promoter. Consistent with this, methylation-specific PCR (MSP) and bisulphite sequencing of regions within the large CpG island located at the 59 end of Bim revealed significant methylation of CpG dinucleotides in all EBV-positive, but not EBV-negative B cells examined. Genomic DNA samples exhibiting methylation of the Bim promoter included extracts from a series of explanted EBV-positive Burkitt’s lymphoma (BL) biopsies. Subsequent analyses of the histone modification H3K27-Me3 (trimethylation of histone H3 lysine 27) and CpG methylation at loci throughout the Bim promoter suggest that in EBV-positive B cells repression of Bim is initially associated with this repressive epigenetic histone mark gradually followed by DNA methylation at CpG dinucleotides. We conclude that latent EBV initiates a chain of events that leads to epigenetic repression of the tumour suppressor gene Bim in infected B cells and their progeny. This reprogramming of B cells could have important implications for our understanding of EBV persistence and the pathogenesis of EBV-associated disease, in particular BL.en_US
dc.languageEnglishen_US
dc.language.isoEnglishen_US
dc.publisherPUBLIC LIBRARY SCIENCEen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleEpstein-Barr Virus Latency in B Cells Leads to Epigenetic Repression and CpG Methylation of the Tumour Suppressor Gene Bimen_US
dc.typeJournal Article
rioxxterms.versionofrecord10.1371/journal.ppat.1000492en_US
rioxxterms.licenseref.startdate2009-06en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfPLOS PATHOGENSen_US
pubs.notesaffiliation: Paschos, K (Reprint Author), Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Virol, London, England. Paschos, Kostas; Anderton, Emma; White, Robert E.; Allday, Martin J., Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Virol, London, England. Smith, Paul, Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. Middeldorp, Jaap M., Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands. article-number: e1000492 keywords-plus: BURKITTS-LYMPHOMA; DNA METHYLATION; 20S PROTEASOME; II RECEPTOR; EXPRESSION; CANCER; MYC; DISEASE; LINES; ACTIVATION research-areas: Microbiology; Parasitology; Virology web-of-science-categories: Microbiology; Parasitology; Virology author-email: m.allday@imperial.ac.uk orcid-numbers: Middeldorp, Jaap/0000-0002-0765-4125 funding-acknowledgement: Wellcome Trust [077489] number-of-cited-references: 54 times-cited: 90 usage-count-last-180-days: 0 usage-count-since-2013: 4 journal-iso: PLoS Pathog. doc-delivery-number: 476LZ unique-id: ISI:000268444500008 oa: gold da: 2018-08-29en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.volume5en_US
pubs.embargo.termsNot knownen_US
dc.contributor.icrauthorSmith, Paulen_US


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