EPSRC-SFI: Supercoiling-driven gene control in synthetic DNA circuits

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One of the central aims of synthetic biology is to use our growing understanding of gene expression to `rewire' bacterial cells so that they exhibit designed behaviour under specific conditions. Supercoiling, a structural transition in the DNA, is a key process in gene expression that has yet to be incorporated into synthetic biology's computational design tools. We have identified a series of exemplar bacterial switches that are controlled by supercoiling, which will be used to guide and validate physical and computational models.Our overarching vision is to develop a synthetic biology toolkit, which we call TORC, that includes the information processing capabilities of DNA supercoiling, and its programmatic modulation. The TORC toolkit will be based on a physical model that captures the mechanism of information processing through DNA supercoiling, and an abstract computational model that will provide both an engineering development approach for advanced synthetic biology applications, and a scientific language for modelling biological genetic processes. This cross-disciplinary project brings together Physics, Biology, and Computer Science to implement the initial steps towards this vision: TORC1.0, a new computational language developed through physical simulations and wet-lab experiments.Our programme has three stages:(i) We will place well-characterised bacterial switches within a single, controllable plasmid, where they will be expressed in bacteria. (ii) We will use well-established statistical physics models of DNA transcription to construct a model of each switch, predict how the output will change with varying biological conditions, and validate it against the wet-lab results.(iii) We will use the validated physical model and wet-lab results to derive a novel computational model of supercoiling, supporting a new computational language for programming synthetic biology designs and applications.