Topology-Dependent Interference of Circuit Function by Growth Feedback

Abstract

Growth-mediated feedback between synthetic gene circuits and host organisms leads to diverse emerged behaviors, including growth bistability and enhanced ultrasensitivity. However, the range of possible impacts of growth feedback on different gene circuits remains underexplored. Here, we mathematically and experimentally demonstrated that growth feedback affects the functions of memory gene circuits in a network topology-dependent way. Specifically, the memory of the self-activation circuit is quickly lost due to the fast growth-mediated dilution of the circuit products.Decoupling of growth feedback reveals its memory, manifested by its hysteresis property across a broad range of stimulus. On the contrary, the toggle switch is more refractory to the growthmediated dilution and can retrieve its memory after the fast-growth phase. The underlying principle lies in the different dependence of active and repressive regulations in these circuits on the growth-mediated dilution. Our results unveil the topology-dependent mechanism on how growth-mediated feedback influences the behaviors of gene circuits.

Emergent Damped Oscillation Induced by Nutrient-Modulating Growth Feedback

“…Unexpected Oscillatory Dynamics Induced by Growth Feedback with Varied Nutrition Level. In our previous work, 19 we built a simple synthetic self-activation (SA) gene circuit (Figure 1A), in which the transcription factor AraC activates the expression of itself by binding to its promoter P BAD . Reporter gene green fluorescent protein (GFP) was used to visualize the dynamics of AraC.…”

“…However, we found that the circuit did not exhibit hysteresis even as a stable bimodal distribution was observed. 19 The underlying reason is that the gene circuits interact with the host cell growth (Figure 1A), which led to the loss of memory for the self-activation circuit after diluting the activated cells into the fresh 100% Lysogeny broth (LB) rich medium. 19 The memory can be maintained well with the M9 minimal culture low-nutrient (0% LB) medium.…”

“…Recently, we found a topology-dependent interference of synthetic gene circuit function by growth feedback. 19 We tested two synthetic memory circuits, selfactivation switch and toggle switch, and found that both circuits interact with host cells through growth feedback but behave differently. While the self-activation switch quickly lost its memory due to the fast dilution of circuit products mediated by host cell growth, the toggle switch is more robust to the growth feedback and retains its memory after the fast growth phase.…”

“…Here we studied how the growth feedback and its effects on gene circuits are modulated by nutrient level. Followed by our previous work, 19 we diluted the cells with an activated selfactivation switch into the fresh medium with reduced nutrition level with a high dose of inducer L-ara. It is surprising to us that the circuit expression level showed very unexpected damped oscillatory dynamics in a broad range of nutrition levels.…”

Frequency dependent growth of bacteria in living materials

“…However, these studies have also revealed gaps in our understanding of how bacteria integrate temporally and spatially heterogeneous signals into beneficial phenotypic changes (Kandemir et al, 2018;Sanfilippo et al, 2019). There have been explorations of the connections between spatial structure and information processing in microbial colonies (Alnahhas et al, 2019;Bittihn et al, 2020;Dal Co et al, 2020;Gupta et al, 2020;Kong et al, 2017;Kussell and Leibler, 2005;van Vliet et al, 2018;Zhang et al, 2021), but these studies have not addressed the information processing of microbes embedded in three-dimensional synthetic materials. Along this line, studies using engineered cells suggest that phenomena like Turing patterns may facilitate collective decision-making based on spatial and temporal information (Cao et al, 2016;Karig et al, 2018).…”