BSc (Hons) Applied Biology 1989
D.Phil Biochemistry 1992
1995 ICRF Postdoctoral Fellowship
1993 Human Frontiers in Science Program Organisation Postdoctoral Fellowship
1989 Gatsby Charitable Foundation Prize Studentship
There are two areas of interest in my laboratory, (1) the function of HIRA nucleosome assembly factors and (2) the regulation of zinc-responsive gene expression.
HIRA Nucleosome Assembly Factors: Packaging of DNA into chromatin is essential for the organization of eukaryotic genomes. However, a variety of DNA dependent processes such as replication, transcription, recombination and repair can disrupt this packaging and so factors that mediate chromatin assembly are required to maintain genomic integrity. We are studying the function of HIRA histone chaperones that mediate the assembly of nucleosomes, the primary subunit of chromatin.
Cells lacking HIRA proteins have dysfunctional heterochromatin that results in a high frequency of "lagging" chromosomes during mitosis. The figure shows an example of an anaphase cell with a lagging chromosome. Spindles are stained green and DNA is stained blue. The lagging chromosome is indicated by an arrow.
HIRA proteins have been highly conserved throughout evolution and so we are use the fission yeast, Schizosaccharomyces pombe as a model system for our analyses. Our recent work has revealed that HIRA proteins are required for the function of repressive chromatin at number of loci. These factors are required for the integrity of pericentric heterochromatin and as a result accurate chromosome segregation. HIRA proteins are also required at other heterochromatic loci and furthermore microarray analysis has identified a set of euchromatic genes whose expression is also silenced in a HIRA-dependent manner.
Current work is directed toward the identification of novel factors that function in concert with HIRA proteins. We are also dissecting how HIRA proteins contribute to the propagation of chromatin structures both at euchromatic target genes and at heterochromatic loci.
Zinc Responsive Gene Expression: Zinc plays vital roles in a range of cellular processes and consequently failure to maintain an adequate level of this metal can result in a range of adverse effects. Nonetheless, excess zinc is toxic and so cells must therefore monitor their intracellular zinc levels and respond when the concentrations fall outside an acceptable range. An important component of this response operates at the level of gene expression, as zinc imbalance elicits the coordinate induction of genes encoding proteins that provide a selective advantage under such conditions. At present the mechanisms by which eukaryotic cells coordinate such gene expression is poorly understood. Therefore, we are using fission yeast to identify and characterise zinc-responsive transcription factors and signalling pathways.
Research in my laboratory is currently funded by Grants from the BBSRC, The Wellcome Trust and Cancer Research UK