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An integrative circuit–host modelling framework for predicting synthetic gene network behaviours

Abstract

One fundamental challenge in synthetic biology is the lack of quantitative tools that accurately describe and predict the behaviours of engineered gene circuits. This challenge arises from multiple factors, among which the complex interdependence of circuits and their host is a leading cause. Here we present a gene circuit modelling framework that explicitly integrates circuit behaviours with host physiology through bidirectional circuit–host coupling. The framework consists of a coarse-grained but mechanistic description of host physiology that involves dynamic resource partitioning, multilayered circuit–host coupling including both generic and system-specific interactions, and a detailed kinetic module of exogenous circuits. We showed that, following training, the framework was able to capture and predict a large set of experimental data concerning the host and its foreign gene overexpression. To demonstrate its utility, we applied the framework to examine a growth-modulating feedback circuit whose dynamics is qualitatively altered by circuit–host interactions. Using an extended version of the framework, we further systematically revealed the behaviours of a toggle switch across scales from single-cell dynamics to population structure and to spatial ecology. This work advances our quantitative understanding of gene circuit behaviours and also benefits the rational design of synthetic gene networks.

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Fig. 1: An integrative view of synthetic circuits and their host.
Fig. 2: Characterization of the coarse-grained E. coli host model.
Fig. 3: Circuit–host interactions.
Fig. 4: Evaluation of model predictability and translatability.
Fig. 5: Integrative modelling of a non-cooperative positive feedback circuit22.
Fig. 6: Integrative modelling of a toggle switch across multiple scales.

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Acknowledgements

This work was supported by the National Science Foundation (No. 1553649 and 1227034), the Office of Naval Research (No. N000141612525), the American Heart Association (No. 12SDG12090025), the Brain and Behavior Research Foundation (NARSAD Young Investigator Award), and the National Center for Supercomputing Applications (Faculty Fellowship).

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T. L. conceived and directed the study and designed the research. C.L. and A.E.B. contributed to model development. C.L., A.E.B. and T.L. analysed data. T.L. and C.L. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Ting Lu.

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Supplementary Methods, Supplementary Tables 1–4, Supplementary Figures 1–32, Supplementary References.

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Liao, C., Blanchard, A.E. & Lu, T. An integrative circuit–host modelling framework for predicting synthetic gene network behaviours. Nat Microbiol 2, 1658–1666 (2017). https://doi.org/10.1038/s41564-017-0022-5

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