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Negatively Competitive Incoherent Feedforward Loops Mitigate Winner-Take-All Resource Competition.
Austin Stone1, Jordan Ryan2, Xun Tang2
1School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona85281, United States.
ACS Synthetic Biology
|November 10, 2022
Summary
Synthetic gene circuits in host organisms face resource limitations. This study shows negatively competitive regulatory (NCR) controllers in incoherent feedforward loops (iFFLs) effectively manage resource competition for better circuit function.
Area of Science:
- Synthetic Biology
- Systems Biology
- Genetic Engineering
Background:
- Host resource limitations significantly impact synthetic gene circuit performance.
- Synthetic genetic programs can impose a burden on host cellular resources.
- Previous work proposed local, global, and negatively competitive regulatory (NCR) controllers for dynamic circuits.
Purpose of the Study:
- To analyze resource allocation strategies for incoherent feedforward loop (iFFL) topologies.
- To evaluate the efficacy of three controller archetypes (local, global, NCR) in iFFLs.
- To investigate the "coactivation threshold shift" effect in iFFL controllers.
Main Methods:
- Mathematical modeling and simulation of resource allocation strategies in iFFL topologies.
- Analysis of Winner-Take-All resource competition dynamics between bistable switches.
- Comparative evaluation of local, global, and NCR controller performance within iFFLs.
Main Results:
- All three iFFL controllers (local, global, NCR) successfully attenuated Winner-Take-All resource competition.
- NCR iFFL controllers demonstrated superior efficacy compared to local controllers, with global controllers being less effective.
- A novel "coactivation threshold shift" effect was observed in iFFL controllers, coupling switch activation thresholds.
- Achieved near-complete orthogonality between bistable switches using an NCR controller and optimized resource consumption.
Conclusions:
- Negatively competitive regulatory (NCR) controllers are highly effective in managing resource competition within incoherent feedforward loop (iFFL) synthetic gene circuits.
- The parameters governing synthetic competition in NCR controllers are critical for their enhanced performance.
- Incoherent feedforward loop (iFFL) topologies exhibit unique regulatory behaviors, including the "coactivation threshold shift" effect.
- NCR controllers offer a promising strategy for achieving orthogonal bistable switches in synthetic biology applications.
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