Biochemistry and Molecular Biology
Subject Group funded PhD studentships
September 2013
Host genes targeted by Epstein Barr virus during replication
– Prof Alison J. Sinclair
Epstein-Barr virus (EBV) is an important human pathogen associated with
nasopharyngeal
carcinoma,
B-cell-lymphomas,
Hodgkin’s
disease,
lymphoproliferative diseases and infectious mononucleosis. Lytic replication of EBV
in B-cells and epithelial cells produces the virions that allow EBV to spread between
cells and individuals, and stimulation of lytic replication of EBV within tumours is
being explored as a mode of oncolytic cancer therapy.
The master regulator of lytic EBV replication is the viral transcription and replication
protein Zta (also known as ZEBRA, BZLF1, EB1) encoded by the BZLF1 gene. Zta
has the ability to both activate and repress gene expression through direct interaction
with a core 7-nucleotide Zta response element (ZRE) in viral and host genes or via
indirect cellular DNA binding proteins (eg C/EBP alpha and p53).
The PhD student will identify host genes directly regulated by Zta arrays in epithelial
cells undergoing lytic cycle using genome-wide approaches of ChIP-Seq and
transcriptomics and determine their contribution to EBV replication.
This project represents an opportunity to couple cell biology with state-of-the-art
genomics. The initial discovery phase will lead to an opportunity for the student to
select which areas of biology - identified within the Zta regulated target genes - they
focus their detailed analysis.
Project
enquiries
should
be
sent
to
Prof.
Alison
Sinclair
(A.J.Sinclair@sussex.ac.uk)
Methods for demonstrating target engagement for novel CNS drugs
- Prof John Atack
The newly-formed Translational Drug Discovery Group, which is a part of the School
of Life Sciences, aims to develop novel drugs for the treatment of a variety of
diseases within the infectious disease, oncology and neuroscience areas. A key aspect
of the development of any neuroscience drug is that of target engagement; in other
words, being able to demonstrate that a drug get into the brain and binds to the target
of interest (whether that be an enzyme, a G-protein coupled receptor or an ion
channel).
The successful student will be involved in developing methods to demonstrate
receptor occupancy assays for the neuroscience projects within the Translational Drug
Discovery Group. More specifically, the student will apply the principles of in vitro
radioligand binding to rat brain receptors, enzymes or ion channels to rat brain
samples using either ex vivo or in vitro binding techniques. The student will also be
exposed to various aspects of the drug discovery process and will be expected to be a
key contributor to a variety of different projects.
Please send all project enquiries to Prof. John Atack (J.Atack@sussex.ac.uk)
Investigating the mechanism of B-cell reprogramming by the cancerassociated Epstein-Barr virus
– Dr Michelle J. West
Epstein-Barr virus (EBV) is associated with the development of numerous human
cancers. The overall aim of our research is to determine how EBV immortalises Bcells and promotes tumourigenesis (McClellan et al., 2012, Palermo et al., 2011,
Schlick et al., 2011). Our specific focus concerns how four key EBV-encoded
transcription factors (Epstein-Barr nuclear antigens (EBNA) 2, 3A, 3B and 3C) drive
epigenetic reprogramming of the host cell. These EBV transcription factors do not
bind DNA directly and hijack B-cell specific transcription factors to deregulate gene
expression.
We have carried out chromatin-immunoprecipitation coupled with next-generation
sequencing to identify cellular gene targets and regulatory elements bound by EBV
transcription factors. We have revealed new target genes relevant to immortalisation
and identified long-range enhancer elements as the predominant targets of these
factors. Our data have also implicated new cellular proteins in targeting EBNA 2 and
3 proteins to DNA.
This project will use genome-wide, molecular biology, biochemical and structural
biology approaches to examine the mechanism of cellular reprogramming by EBV
transcription factors. The research will focus on (i) determining the role and function
of long-range enhancers (ii) determining the role and mechanism of interplay between
EBV transcription factors (iii) obtaining structural and functional information on the
complexes formed between EBV transcription factors and cellular DNA binding
proteins in collaboration with Dr Prodromou (Xu et al., 2012, Zhang et al., 2010)
Project enquiries should be sent to project supervisor Dr Michelle West
(M.J.West@sussex.ac.uk)
Applicants should hold or expect to hold qualifications at the level of, or equivalent
to, a first or upper class second honours degree from a UK institution. Formal
applications should be made using our online application system at
http://www.sussex.ac.uk/study/pg/applying/
Please mention the name of the
principal investigator as the suggested supervisor in the application.
Please also send a full CV, degree results or marks to date and names of 2 academic
referees directly to the proposed supervisor.