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Gene Regulation: How mammalian genes are switched on and off during development and differentiation and how this goes awry in human genetic diseases


Project Description

Other Potential Supervisors: Mira Kassouf

Our laboratory addresses the question of how mammalian genes are switched on and off during development, lineage commitment and differentiation. We use genomics technologies and computational approaches to study both the entire genome and individual genes in detail. We study all aspects of gene expression including the key cis-regulatory elements (enhancers, promoters and insulators), the transcription factors and co-factors that bind them, the epigenetic modifications of chromatin and DNA, and the role of associated phenomena such as chromosome conformation and nuclear sub-compartmentalisation using state-of-the-art imaging techniques. These studies are performed both in cell systems and in model organisms and using material from human patients with inherited and acquired, genetic and epigenetic abnormalities. The translational goal of our work is to develop new ways to modify gene expression during blood formation with the aim of manipulating gene expression and ameliorating the clinical phenotypes of patients with a variety of blood disorders.

We study gene regulation using the human and mouse globin loci as haematopoietic cells undergo development, lineage fate decisions and differentiation. Globin gene expression is controlled by a group of conserved, long-range regulatory elements. All of these elements have the chromatin signature of enhancers which physically interact with each other and with the globin gene promoters, to activate globin gene expression. This configuration appears to be a common feature of highly expressed, lineage-specific genes and such groups of regulatory elements are referred to as “super-enhancers”. We study such enhancers to understand how they interact with the globin promoters and their effect on the transcription cycle. More recently we have developed imaging which allows us to visualise transcription of these genes in real time.

We have recently performed Hi-C experiments to define the Topologically Associated chromatin Domain (TAD) containing the globin gene cluster in erythroid and non-erythroid cells. We are currently investigating how activation, deletion and re-orientation of the globin regulatory elements affect expression of other genes within the same TAD and in neighbouring TADs. We also study chromatin structure and movement in real time using super-resolution imaging. Using globin as our model, we address the relationship between higher order, long-range chromosomal structure and function.

In addition to understanding how genes are activated we are also interested in how they are silenced. One of the globin genes, lying within the TAD, is only expressed in early developmental life and then remains silenced during adult life. We are studying the transcriptional and epigenetic pathway by which this gene is silenced and kept so even though it lies adjacent to active erythroid enhancers. Again this is a general question in mammalian genetics and the globin system provides a unique opportunity to establish the principles by which gene silencing occurs.

An important aim of our work is to develop new ways of treating blood disorders by genome editing of the regulatory elements we are studying. We currently have clinical projects underway in Sri Lanka and Thailand to develop such techniques to treat patients with thalassaemia, a common form of inherited anaemia.

Our laboratory offers a wide range of training opportunities in cell biology, molecular biology and computational biology. We use flow cytometry to isolate and characterise common and rare cell types including stem/progenitor cells. When required, we also train students in mouse genetics. Molecular techniques used in the laboratory include all forms of sequence-based analysis of DNA and chromatin (ATAC-seq, RNA-seq, Net-seq, scaRNA-seq etc). We also have access to the full range of proteomics and structural biology. The laboratory has also pioneered high resolution protocols for chromosomal conformation capture. All methods are applied to populations of cells and single cells. We routinely use genome editing, advanced forms of homology directed recombination, and synthetic biology. An important new dimension to our research involves the use of advanced imaging, including super-resolution imaging, particularly in real time. Students interested in such projects will receive appropriate training in all techniques.

As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Funding Notes

Our main deadline for applications for funded places has now passed. Supervisors may still be able to consider applications from students who have alternative means of funding (for example, charitable funding, clinical fellows or applicants with funding from a foreign government or equivalent). Prospective applicants are strongly advised to contact their prospective supervisor in advance of making an application.

Please note that any applications received after the main funding deadline will not be assessed until all applications that were received by the deadline have been processed. This may affect supervisor availability.

References

A tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions. Brown JM, Roberts NA, Graham B, Waithe D, Lagerholm C, Telenius JM, De Ornellas S, Oudelaar AM, Scott C, Szczerbal I, Babbs C, Kassouf MT, Hughes JR, Higgs DR, Buckle VJ. Nat Commun. 2017


Between form and function: the complexity of genome folding. Oudelaar AM, Hanssen LLP, Hardison RC, Kassouf MT, Hughes JR, Higgs DR.. Hum Mol Genet. 2017


Hanssen LLP, Kassouf MT, Oudelaar AM, Biggs D, Preece C, Downes DJ, Gosden M, Sharpe JA, Sloane-Stanley JA, Hughes JR et al. 2017. Tissue-specific CTCF-cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo. Nat Cell Biol 19: 952-961.


Hay D, Hughes JR, Babbs C, Davies JOJ, Graham BJ, Hanssen L, Kassouf MT, Oudelaar AM, Sharpe ja, Suciu M, Telenius J, Williams R, Rode C, Li P-S, Pennacchio LA, Sauka-Spengler T, Sloane-Stanley JA, Ayyub H, Butler S, Gibbons RJ, Smith AJH, Wood WG & Higgs DR (2016) Testing the super-enhancer concept by in-vivo dissection. Nature genetics, 48, 895-903.


Hughes, J.R., Roberts, N., McGowan, S., Haay, D., Giannoulatou, E., Lynch, M., de Gobbi, M., Taylor, S., Gibbons, R. & Higgs, D.R. (2014) Analysis of hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput experiment. Nat Genet, 46: 205-212.


Kowalczyk, M., S., Hughes, J.R., Garrick, D., Lynch, M.D., de Gobbi, M., McGowan, S.J., Brown, J.M., Hosseini, M., Sharpe, J.A., Sloane-Stanley, J.A., Gray, N.E., Collavin, L., Gibbons, R.J., Flint, J., Taylor, S., Buckle, V.J., Wood, W.G. & Higgs, D.R. (2012) Intragenic enhancer-like elements act as alternative promoters. Mol Cell, 45, 447-458

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