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An investigation of the epigenetic and transcriptional changes which follow Epstein-Barr virus infection of germinal centre B cells

Leonard, Sarah Miriam (2010)
Ph.D. thesis, University of Birmingham.

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Abstract

Although Epstein–Barr virus (EBV) usually establishes a harmless infection in human memory B cells, it is implicated in the development of germinal centre (GC) B-cell-derived malignancies, including Hodgkin’s lymphoma (HL). I have shown using gene expression profiling that lymphoblastoid cell lines derived from GC B cells are a useful model for studying early EBV-associated changes contributing to the pathogenesis of HL. EBV infection of GC B cells is followed by the up-regulation of the DNA methyltransferases, DNMT3A, and the down-regulation of DNMT1 and DNMT3B, a pattern of expression which is re-capitulated in HL cell lines. I have also shown that the major EBV oncogene, LMP1, is responsible for the down-regulation in GC B cells of DNMT1, and that DNMT3A binds to the EBV promoter, Wp which is silenced by DNA methylation. Genome-wide promoter arrays revealed that EBV infection of GC B cells is followed by methylation changes in a substantial number of cellular genes. These changes were not randomly distributed across the genome but clustered at certain chromosomal locations and were strongly associated with the CpG content of gene promoters. Finally, I have shown that EBV also modulates the expression of another set of epigenetic regulators which control arginine methylation.

Type of Work:Ph.D. thesis.
Supervisor(s):Woodman, Ciaran BJ and Murray, Paul and Wei, Wenbin
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Cancer Sciences
Subjects:QR355 Virology
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Institution:University of Birmingham
ID Code:1200
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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