School of Life Sciences

West Lab

Cancer cells Samples for an experiment Results of an experiment

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 partcular interest in how RGC-32 expression is controlled both transcriptionally and post-transcriptionally and how this contributes to tumour development.

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 Bloodwise and the Medical Research council.

Click here to hear Michelle talk about her Bloodwise funded research on lymphoma

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We are also very grateful for previous fellowship and grant funding from the Wellcome Trust, the Royal Society and Studentship support from the BBSRC.

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Contact details

Professor Michelle West

 

Woman Scientist

Professor of Tumour Virology

School of Life Sciences
University of Sussex
John Maynard Smith Building
Falmer
Brighton, BN1 9QG

E M.J.West@sussex.ac.uk

T +44 1273 678404 (office)
T +44 1273 678683 (lab)
F +44 1273 877586

go to Michelle West's profile