4.8 Article

Winner-takes-all resource competition redirects cascading cell fate transitions

Journal

NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -

Publisher

NATURE RESEARCH
DOI: 10.1038/s41467-021-21125-3

Keywords

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Funding

  1. ASU School of Biological and Health Systems Engineering
  2. NSF [EF-1921412]
  3. Arizona State University Dean's Fellowship

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Resource competition between gene circuit modules can lead to unexpected circuit functions. By building cascading bistable switches to achieve two successive cell fate transitions, a 'winner-takes-all' behavior was observed which was overcome by a division of labor strategy.
Failure of modularity remains a significant challenge for assembling synthetic gene circuits with tested modules as they often do not function as expected. Competition over shared limited gene expression resources is a crucial underlying reason. It was reported that resource competition makes two seemingly separate genes connect in a graded linear manner. Here we unveil nonlinear resource competition within synthetic gene circuits. We first build a synthetic cascading bistable switches (Syn-CBS) circuit in a single strain with two coupled self-activation modules to achieve two successive cell fate transitions. Interestingly, we find that the in vivo transition path was redirected as the activation of one switch always prevails against the other, contrary to the theoretically expected coactivation. This qualitatively different type of resource competition between the two modules follows a 'winner-takes-all' rule, where the winner is determined by the relative connection strength between the modules. To decouple the resource competition, we construct a two-strain circuit, which achieves successive activation and stable coactivation of the two switches. These results illustrate that a highly nonlinear hidden interaction between the circuit modules due to resource competition may cause counterintuitive consequences on circuit functions, which can be controlled with a division of labor strategy. Synthetic gene circuits may not function as expected due to the resource competition between modules. Here the authors build cascading bistable switches to achieve two successive cell fate transitions but found a 'winner-takes-all' behaviour, which is overcome by a division of labour strategy.

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