This 4-year joint Crick PhD studentship is offered in the labs of Dr Nicholas Luscombe & and Dr James Briscoe’s Group based at the Francis Crick Institute (the Crick).
How are the right types of cells produced in the right place, at the right time, in the right amounts in a developing tissue? We study these questions in the developing spinal cord, which, despite its complexity, is assembled in a remarkably precise and reliable manner. This precision is necessary for the wiring of nerves into the neural circuits that gives the spinal cord its function.
Development of tissues such as the central nervous system depends on the precise spatial and temporal regulation gene expression to control the identity and proliferation of differentiating cells. Using a range of molecular, imaging and modelling approaches that combine single cell resolution dynamic assays of signaling, cell fate specification, chromatin structure and gene activity we are examining the mechanism of gene regulation in neural progenitors. Central to the regulation of gene activity are cis regulatory elements (CREs). These are the functional control elements and represent the information processing apparatus that receive and integrate transcriptional and signalling inputs to control gene expression outputs. Despite their importance, how CREs encode their gene regulation function and convert transcription factor inputs into gene expression is poorly understood. We employ novel computational tools and dynamical systems models to obtain a comprehensive of gene regulation in neural tube development and to analyze the interdependence between different aspects of pattern formation. For our experimental studies we use a range models including mouse and chick embryos and mouse and human embryonic stem cells. For data analysis, we apply advanced statistical modelling approaches.
This project, which is a collaboration between computational and experimental groups, will systematically test and manipulate CREs in neural progenitors using genome editing to delete or alter the endogenous CREs of a target gene. The results will allow us to refine or refute models of gene regulation in the iterative cycle of experiment and model validation. Guided by predictions from the mathematical models we will prioritize and extend this strategy to develop a predictive understanding of CRE activity. The analysis will provide insight into the transcriptional control mechanisms governing gene regulation. Moreover, the approach will establish a toolbox comprising computational models, transcriptional network analysis and stem cell differentiation for the re-engineering of spinal tissue. Our ambition is to make predictable changes to the spatial patterns of gene expression in the neural tube by precise alterations of a CRE.
The project offers interdisciplinary training in cutting edge techniques in stem cell and developmental biology, computational biology and statistical modelling. It will provide quantitative insight into the mechanisms and principles of the gene regulatory programmes that underpin tissue development. This will contribute to understanding the development of the spinal cord as well as shed light on the diseased and damaged nervous systems.
This project would suit a candidate interested in receiving interdisciplinary training in computational biology and developmental biology and will involve both experimental work and statistical modelling.
Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2020 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).
Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.
APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) 13 NOVEMBER 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.
1. Metzis, V., Steinhauser, S., Pakanavicius, E., Gouti, M., Stamataki, D., Ivanovitch, K., . . . Briscoe, J. (2018)
Nervous system regionalization entails axial allocation before neural differentiation.
Cell 175: 1105-1118.e1117. PubMed abstract
2. Sagner, A., Gaber, Z. B., Delile, J., Kong, J. H., Rousso, D. L., Pearson, C. A., . . . Novitch, B. G. (2018)
Olig2 and Hes regulatory dynamics during motor neuron differentiation revealed by single cell transcriptomics.
PLOS Biology 16: e2003127. PubMed abstract
3. Zagorski, M., Tabata, Y., Brandenberg, N., Lutolf, M. P., Tkačik, G., Bollenbach, T., . . . Kicheva, A. (2017)
Decoding of position in the developing neural tube from antiparallel morphogen gradients.
Science 356: 1379-1383. PubMed abstract
4. Crocker, J. and Ilsley, G. R. (2017)
Using synthetic biology to study gene regulatory evolution.
Current Opinion in Genetics & Development 47: 91-101. PubMed abstract
5. Ilsley, G. R., Fisher, J., Apweiler, R., De Pace, A. H. and Luscombe, N. M. (2013)
Cellular resolution models for even skipped regulation in the entire Drosophila embryo.
eLife 2: e00522. PubMed abstract