Dr R Roychoudhuri
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
T cells coordinate immune function by differentiating into highly specialised cellular lineages that either promote or suppress immune reactions. Whereas effector T cells cause immune activation and can drive clearance of infections and cancer, regulatory T cells, dependent upon the transcription factor Foxp3, suppress their function, preventing excessive immune reactions but promoting deleterious immunosuppression in cancer. Thus, T cells play a pervasive role in health and disease but mechanisms that control induction and stability of effector and regulatory cells are incompletely elucidated [1]. Their discovery will enable development of a powerful new class of therapies.
Enhancers form higher-order looping structures with sometimes distant genes to regulate gene transcription and programme cell-specific transcriptional outputs [2]. Genetic variations that contribute to risk of autoimmune and allergic diseases are highly enriched at enhancers, indicating their potential involvement in regulation of immune function [3]. We have recently identified a transcription factor protein, BACH2, that functions as a pervasive regulator of immune activation, promoting the development of regulatory T cells while suppressing the differentiation and function of multiple effector lineages [4]. Genetic polymorphisms within the BACH2 locus are associated with susceptibility to several autoimmune and allergic diseases in humans and deletion of BACH2 in mice results in spontaneous lethal inflammation. New data indicates that BACH2 predominantly binds genomic enhancers that lie at great distances from known protein-coding genes [5], but mechanisms of its action at enhancers are unclear.
We hypothesise that binding of BACH2 to enhancers is central to its role in regulating immune function. This project will utilize cutting edge conditional mouse genetics and a variety of approaches in molecular biology, functional genomics and higher-order chromatin structure to resolve mechanisms by which BACH2 controls regulatory cell fate-specification and stability from genomic enhancers. Using infectious disease and tumor models, the applicant will assess consequences of enahancer disruption in vivo. The applicant will therefore gain experience in a variety of cutting-edge technical and scientific approaches. The project unites several key areas of expertise in which the Babraham Institute has established a world-class reputation, including lymphocyte development, nuclear dynamics and epigenetics. The student will join a dynamic and collaborative research group within the Lymphocyte Signaling and Development ISP and will benefit from extensive collaborations with researchers at the Nuclear Dynamics ISP at Babraham.
For more information on the work of the laboratory, please visit: http://www.babraham.ac.uk/our-research/lymphocyte/rahul-roychoudhuri
References
1. O’Shea, et al. (2010). Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327:1098-102.
2. Maurano, et al. (2012). Systematic localization of common disease-associated variation in regulatory DNA. Science 337:1190-5.
3. Nagano, et al. (2013). Single-cell Hi-C reveals cell-to-cell variability in chromosome structure. Nature 502:59-64.
4. Roychoudhuri, et al. (2013). BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis. Nature 498; 506-10.
5. Vahedi, et al. (2015). Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature 520:558-62.