The Smith Group at the Medical Research Council-Wellcome Trust Stem Cell Institute in Cambridge, in partnership with the Computational Biology Group at Microsoft Research, offers an exciting interdisciplinary 4-year PhD studentship commencing October 2017.
Decoding the network logic for resetting pluripotency
- Interdisplinary project at the interface of stem cell research and computational modelling
- Delineation of network trajectories for cellular reprogramming at single cell resolution
- Combination of wetlab research with logical modelling
- Collaboration between the laboratory of Prof. Austin Smith and Microsoft Research Cambridge
The pluripotent ground state of embryonic stem cells (ESCs) is governed by a self-reinforcing interaction network of transcription factors (Dunn et al, Science 2014). Combinations of factors within this network can induce somatic cells to acquire pluripotency, a process called molecular reprogramming (Takahashi and Yamanaka, Cell, 2006). Experimental and computational efforts have led to circuitry mapping of the key players in maintenance of the ESC state. However, how this molecular circuitry is launched and fully connected during reprogramming remains unclear. This project is a cross-disciplinary investigation to address systematically how cells transit to the pluripotent ESC state at the molecular network level. The multi-step, heterogeneous and asynchronous nature of the reprogramming process presents technical challenges. This project is designed to overcome these challenges by using a minimal reprogramming system and integrating quantitative single-cell gene expression profiling at defined reprogramming stages with computational network synthesis and modelling. This approach will transform a temporal series of single-cell snapshots of network status into reconfiguring network trajectories. Predictions formulated from the synthesised trajectores will be tested experimentally and the results used for iterative refinement of the model set.
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