Emergent Damped Oscillation Induced by Nutrient-Modulating Growth Feedback

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 emergent 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 damped 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 nutrients, its gene expression first decreases as the cell grows and then shows a significant overshoot before it reaches the steady state, leading to damped 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 toward 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 moderate nutrients, but was not observed in rich nutrients. We experimentally verified this prediction by tuning the nutrient level in the culture medium. We did not observe significant oscillatory behavior for the toggle switch, suggesting that the emergence of damped 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.

Emergence of qualitative states in synthetic circuits driven by ultrasensitive growth feedback

“…Our previous work showed how circuits interact with growth feedback depending on their network topologies [ 21 , 22 ]. Here, we study how the qualitative state of the toggle switch circuit is affected under the ultrasensitive growth feedback.…”

“…For example, if it is nutrient-modulated, which leads to negative regulation, or if it is translation-modulated, which leads to positive regulation [ 18 ]. Recently, we used a coarse-grained model to understand the mechanism of emergent damped oscillation induced by nutrient-modulating growth feedback [ 22 ]. Data fitting and theoretical analysis suggest a nonmonotonic growth-rate regulation of gene production rate [ 22 ].…”

“…The growth feedback has diverse impacts on the gene circuits [18,[20][21][22][23][24][25]. Under some circumstances, growth feedback can be exploited.…”

“…That is, the effects of the growth feedback depend on the gene circuit topologies. Interestingly, Melendez-Alvarez et al reported unexpected damped oscillatory dynamics of the self-activation circuit by modulating growth feedback with nutrient level [ 22 ]. These studies demonstrate how the host growth and circuit interaction can lead to unexpected outcomes depending on the cell condition and gene circuit topologies.…”

Double‐Edged Role of Resource Competition in Gene Expression Noise and Control

“…For future investigation, we intend to look at the noise behavior in more complex and dynamic systems, such as the dual self-activating or cascading circuits that we have analyzed recently. [6,20] The noise from other circuit-host interactions such as growth feedback [60][61][62][63][64][65] adds another layer of complexity to the stochastic gene expression of synthetic circuits. The stochasticity in cellular growth and its propagation to the synthetic gene circuits is another potential source of fluctuations.…”