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Epigenetic mechanisms of gene regulation during blood cell differentiation

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  • Full or part time
    Dr West
  • Application Deadline
    No more applications being accepted
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

A number of common genetic diseases result in in blood disorders and anaemias. Intense research has focussed on gene and cell therapies to treat these diseases, which has produced some successes, but remains very challenging. There are instances where a disorder can be overcome by simply changing gene expression. The most prevalent example is that of thalassaemia, a defect in the α- or β-globin proteins that form haemoglobin in red blood cells, resulting in severe anaemia that is often fatal. Different globin genes are expressed at different stages of development. It is known that reactivation of otherwise silent embryonic or foetal genes can compensate for the defects in the adult genes. Current treatments are only partially effective. More thorough understanding of how genes are regulated during development is required to design better treatments. The precise regulation of cell type-specific genes during development and differentiation involves an interplay between transcription factors that bind to gene promoters and enhancers. These factors assemble epigenetic modification and chromatin remodelling events that enable gene transcription. We are investigating a family of poorly characterised transcription factors that we have found to function at blood genes and are required for normal blood differentiation. You can use our established CRISPR methodologies, whole genome chromatin assays and gene expression profiling to study how these factors work. Our CRISPR effector technology can be used to test your ideas of how gene regulatory patterns can be altered to improve genetic and cellular treatments for blood disorders.

The West research group is home to bright and highly motivated researchers interested in all that is chromatin, epigenetics and CRISPR. We employ a wide range of chromatin, genomic and epigenomic techniques to address fundamental aspects of gene regulation during vertebrate development and human disease. We are located in the state-of-the-art Wolfson Wohl Cancer Research Centre, home of the Institute of Cancer Sciences and world class ’omics facilities.

When applying, please search for the project using ’epigenetic mechanisms’ in the programme description box and select the full programme title as it appears underneath.

Recommended start date is 1 October although this is flexible.

Funding Notes

This project is for self-funded students who have secured their own scholarships. Provide details of your scholarship on application. Contact the supervisor in the first instance.

References

Publications arising from previous postgraduate research students in the group are listed below.
1. Barkess, G., and West, A. G. (2012) Chromatin insulator elements: establishing barriers to set heterochromatin boundaries. Epigenomics, 4 (1). pp. 67-80. (doi:10.2217/epi.11.112)
2. Zhou, Y., Kurukuti, S., Saffrey, P., Vukovic, M., Michie, A.M., Strogantsev, R., West, A.G., and Vetrie, D. (2013) Chromatin looping defines expression of TAL1, its flanking genes, and regulation in T-ALL. Blood, 122 (26). pp. 4199-4209. (doi:10.1182/blood-2013-02-483875)
3. Baxter, E.W. et al. (2013) The inducible tissue-specific expression of the human IL-3/GM-CSF locus is controlled by a complex array of developmentally regulated enhancers. Journal of Immunology, 189 (9). pp. 4459-4469. (doi:10.4049/jimmunol.1201915)
4. Ma, M.K.-W., Heath, C., Hair, A., and West, A. (2011) Histone crosstalk directed by H2B ubiquitination is required for chromatin boundary integrity. PLoS Genetics, 7 (7). e1002175. ISSN 1553-7390 (doi:10.1371/journal.pgen.1002175)
5. Dickson, J., Gowher, H., Strogantsev, R., Gaszner, M., Hair, A., Felsenfeld, G., and West, A. G. (2010) VEZF1 elements mediate protection from DNA methylation. PLoS Genetics, 6 (1). e1000804. (doi:10.1371/journal.pgen.1000804)

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