A model for the spatio-temporal design of gene regulatory circuits

Abstract

The design of increasingly complex gene regulatory networks relies upon mathematical modelling to link the gap that goes from conceptualisation to implementation. An overarching challenge is to update modelling abstractions and assumptions as new mechanistic information arises. Although models of bacterial gene regulation are often based on the assumption that the role played by intracellular physical distances between genetic elements is negligible, it has been shown that bacteria are highly ordered organisms, compartmentalizing their vital functions in both time and space. Here, we analysed the dynamical properties of regulatory interactions by explicitly modelling spatial constraints. Key to the model is the combined search by a regulator for its target promoter via 1D sliding along the chromosome and 3D diffusion through the cytoplasm. Moreover, this search was coupled to gene expression dynamics, with special attention to transcription factor-promoter interplay. As a result, promoter activity within the model depends on its physical separation from the regulator source. Simulations showed that by modulating the distance between DNA components in the chromosome, output levels changed accordingly. Finally, previous experimental results with engineered bacteria in which this distance was minimized or enlarged were successfully reproduced by the model. This suggests that the spatial specification of the circuit alone can be exploited as a design parameter to select programmable output levels.