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Emergent Oscillation Induced by Nutrient-Modulating Growth Feedback

Juan Melendez-Alvarez, Changhan He, Rong Zhang, Yang Kuang, Xiao-Jun Tian
doi: https://doi.org/10.1101/2021.02.09.430447
Juan Melendez-Alvarez
aSchool of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ 85281, USA
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Changhan He
bSchool of Mathematical and Statistical Sciences, Arizona State University, Tempe, AZ 85281, USA
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Rong Zhang
aSchool of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ 85281, USA
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Yang Kuang
bSchool of Mathematical and Statistical Sciences, Arizona State University, Tempe, AZ 85281, USA
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Xiao-Jun Tian
aSchool of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ 85281, USA
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  • For correspondence: Xiaojun.Tian@asu.edu
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Abstract

Growth feedback, the inherent coupling between the synthetic gene circuit and the host cell growth, could significantly change the circuit behaviors. Previously, a diverse array of emerged behaviors, such as growth bistability, enhanced ultrasensitivity, and topology-dependent memory loss, were reported to be induced by growth feedback. However, the influence of the growth feedback on the circuit functions remains underexplored. Here, we reported an unexpected oscillatory behavior of a self-activation gene circuit induced by nutrient-modulating growth feedback. Specifically, after dilution of the activated self-activation switch into the fresh medium with moderate nutrient, its gene expression first decreases as the cell grows and then shows a significant overshoot before it reaches the steady states, leading to oscillation dynamics. Fitting the data with a coarse-grained model suggests a nonmonotonic growth-rate regulation on gene production rate. The underlying mechanism of the oscillation was demonstrated by a molecular mathematical model, which includes the ribosome allocation towards gene production, cell growth, and cell maintenance. Interestingly, the model predicted a counterintuitive dependence of oscillation amplitude on the nutrition level, where the highest peak was found in the medium with a moderate nutrient but was not observed in rich nutrient. We experimentally verified this prediction by tuning the nutrient level in the culture medium. We did not observe significant oscillatory behavior for toggle switch, suggesting that the emergence of oscillatory behavior depends on circuit network topology. Our results demonstrated a new nonlinear emergent behavior mediated by growth feedback, which depends on the ribosome allocation between gene circuit and cell growth.

Competing Interest Statement

The authors have declared no competing interest.

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Posted February 10, 2021.
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Emergent Oscillation Induced by Nutrient-Modulating Growth Feedback
Juan Melendez-Alvarez, Changhan He, Rong Zhang, Yang Kuang, Xiao-Jun Tian
bioRxiv 2021.02.09.430447; doi: https://doi.org/10.1101/2021.02.09.430447
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Emergent Oscillation Induced by Nutrient-Modulating Growth Feedback
Juan Melendez-Alvarez, Changhan He, Rong Zhang, Yang Kuang, Xiao-Jun Tian
bioRxiv 2021.02.09.430447; doi: https://doi.org/10.1101/2021.02.09.430447

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