PhD project: Genome-wide Mechanisms of Gene Regulation and Epigenetic Priming in T Cell Development

Application Deadline: 31 January 2013

Principal Supervisor: Peter Cockerill, University of Birmingham

Due to funding we are only able to accept applications from EU/UK applicants

This project is one of the PhD projects available within the Midlands Integrative Biosciences Training Partnership. This is a 4 year BBSRC funded integrated training program jointly run by the Universities of Birmingham, Warwick and Leicester. Year one is dedicated to training/short projects. The main PhD projects begin in year two.  Applicants are advised to nominate a project supervisor of choice at the time of application.

The project offered by our laboratory investigates mechanisms that allow genes to be expressed in an inducible manner in T cells in response to activation of the immune system. We aim to define gene regulation networks that allow specific types of transcription factors to prime specific sets of genes at the level of chromatin structure, so that they acquire the ability to rapidly respond to immune stimuli. Our previous studies in this area have focussed on the Interleukin-3/GM-CSF locus. These are cytokine genes that are rapidly induced in fully differentiated T cells by T cell receptor (TCR) signalling pathways. We have established that these genes are activated by upstream enhancers that bind the inducible factors AP-1 and NFAT^1,2. However, the ability of T cells to express these genes is dependent on prior priming of the locus by other pathways³. We’ve recently found that the inducible enhancers are non-functional in the absence of other regulatory elements that can maintain an active chromatin environment in memory T cells. These elements remain inactive in naive T cells and in the T cell precursors in the thymus.

Current and future studies are aimed at identifying the transcription factors and regulatory elements that control gene function throughout the genome in T cells. We are performing genome-wide analyses of DNaseI Hypersensitive Sites (DHSs) which represent open regions of chromatin that exists at sites where active or primed regulatory elements exist. We are also performing genome-wide chromatin immuno-precipitation (ChIP) assays to identify which specific transcription factors and histone modifications maintain these DHSs in a primed state prior to TCR activation, and which turn genes on in response to TCR activation. All of these studies require extensive bioinformatics analyses to both process the raw data and map the DNA sequences back to specific genes, and to identify common patterns of factors that define the key regulatory networks.

Stipend allowance £13,590 pa (plus £600 travel allowance in year 1 and a MacBook Pro)

Informal enquiries: Peter Cockerill  p.n.cockerill@bham.ac.uk

Information about the program: http://www.birmingham.ac.uk/research/activity/mibtp/index.aspx

Details on how to apply:

http://www2.warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/application

References:

1.  Baxter EW, Mirabella F, Bowers SR, et al. The Inducible Tissue-Specific Expression of the Human IL-3/GM-CSF Locus Is Controlled by a Complex Array of Developmentally Regulated Enhancers. J Immunol. 2012; 189: 4459-4469.

2.  Johnson BV, Bert AG, Ryan GR, Condina A, Cockerill PN. GM-CSF enhancer activation requires cooperation between NFAT and AP-1 elements and is associated with extensive nucleosome reorganization. Mol Cell Biol. 2004; 24: 7914-7930.

3.  Mirabella F, Baxter EW, Boissinot M, James SR, Cockerill PN. The human IL-3/granulocyte-macrophage colony-stimulating factor locus is epigenetically silent in immature thymocytes and is progressively activated during T cell development. J Immunol. 2010; 184: 3043-3054.