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