Mechanisms of Epstein-Barr virus-driven cellular reprogramming and transformation
The research in our laboratory is focussed on deciphering the mechanisms involved in B-cell transformation by the cancer-associated herpesvirus, Epstein-Barr virus (EBV).
EBV is associated with the pathogenesis of numerous lymphoid tumours including Burkitt’s lymphoma, Hodgkin’s disease, post-transplant lymphoma and certain T-cell and natural killer cell lymphomas, in addition to the epithelial-cell tumour nasopharyngeal carcinoma. The oncogenic properties of the virus are reflected by its ability to immortalise resting B-cells in vitro generating permanently proliferating lymphoblastoid cell-lines (LCLs). Like other members of the herpesvirus family, EBV has a biphasic life cycle involving a latent and lytic phase. In infected B-cells EBV establishes a latent infection where the 172 kb double-stranded DNA viral genome is maintained as a closed circular episome and expresses a limited set of latent gene products. These include the Epstein-Barr nuclear antigens (EBNAs) 1, 2, 3A, 3B, 3C, LP and latent membrane proteins (LMPs) 1, 2A and 2B, the untranslated Epstein-Barr-encoded RNAs EBER 1 and EBER 2 and numerous microRNAs. EBNA 1, 2, 3A, 3C and LMP1 play essential roles in B-cell infection and immortalisation since loss of each of these genes renders viruses incapable of establishing permanently proliferating LCLs in vitro and/or promoting the continued growth of these infected cells.
Despite its cancer-promoting properties, effective immune control combined with restricted expression of only subsets of latent proteins during viral persistence in vivo, enables over 95% of the world’s population to carry EBV as a lifelong asymptomatic infection. EBV infection via the exchange of saliva usually passses unnoticed in early childhood, but if delayed until early adulthood, primary infection can result in the benign lymphoproliferative disease, infectious mononucelosis (glandular fever).
All of the EBNAs function as transcriptional regulators and a key aspect of our research aims to define the molecular mechanisms involved in the regulation of viral and cellular gene transcription by EBV-encoded factors, with a specific focus on the EBNA 2 and the EBNA 3 family of proteins (3A, 3B and 3C). We are particularly interested in the regulation of both viral and cellular transcription by these EBNAs and in their dual roles as transcriptional activators and repressors. Using ChIP-sequencing technology we have mapped the genome-wide binding sites of these key viral proteins in EBV infected cells and have discovered that they predominantly target long-range gene regulatory elements (enhancers). One current area of our research uses chromosome conformation technologies (3C, 4C and capture Hi-C) to study the modulation of enhancer-promoter interactions by the EBNAs at key cellular genes involved in lymphoma development and B cell transformation. We are also studying cellular genes deregulated by EBV in transformed cells, including the cell-cycle regulator and CDK1 binding protein RGC-32. We have a particular interest in understanding the mechanism and consequences of CDK1 activation by RGC-32 and how RGC-32 expression is controlled post-transcriptionally. We are also studying EBV variants and the impact of natural sequence variation on the structure and function of EBV nuclear antigens.
We welcome enquiries from researchers interested in joining our laboratory. Please e-mail Michelle West with your CV and details of your research interests.
Work in our laboratory is currently funded by grants from the Medical Research Council, Blood Cancer UK, Cancer Research UK and the Wellcome Trust
