Sharing Resources Can Lead to Monostability in a Network of Bistable Toggle Switches

György, András

doi:10.1109/lcsys.2018.2871128

Cited by 12 publications

(18 citation statements)

References 26 publications

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“…For instance, we have already seen that in case of balanced toggle switches (i.e.,

), the dynamics are bistable if

[ 61 ], independent of the value of b ( Figure 3 a). In case of unbalanced switches, from ( 12 ) we expect that greater values of a push the dynamics towards monostability by decreasing the right-hand side of ( 12 ), whereas increasing

would have the opposite effect, confirmed in Figure 3 b.…”

Section: Resultsmentioning

confidence: 99%

“…To illustrate the detrimental effects of such competition, consider the collective behavior of N toggle switches, given by the dynamics

where

for

. While a single toggle switch alone may display a bistable stability profile, the addition of further switches decreases the separation of the two stable fixed points ( Figure 1 ), eventually leading to the collectively monostable dynamics of individually bistable toggle switches ( Figure 7 a) as a result of additional loading from each other [ 61 ].…”

Section: Resultsmentioning

confidence: 99%

“…Focusing first on balanced toggle switches (i.e.,

), with

the nullclines

and

intersect three times if

and at a single point otherwise [ 61 ] ( Figure 1 a). Considering the Jacobian of ( 6 ) at these intersections, it was also shown in [ 61 ] that two of them correspond to stable fixed points, whereas the third one gives rise to an unstable equilibrium. As increased resource sequestration yields greater values of

, it pushes the nullclines lower in Figure 1 a, eventually causing the transition from bistability (middle panel in Figure 1 a) to monostability (right panel in Figure 1 a).…”

Section: Materials and Methodsmentioning

confidence: 99%

“…While in the case of balanced toggle switches an equilibrium lies either on the

or on the

manifolds [ 61 ] (middle panel in Figure 1 b), in case of unbalanced switches this is no longer true. In particular, fixed points of ( 6 ) given by the intersections of the nullclines

and

must also satisfy the constraint

as illustrated in the right panel in Figure 1 b (see Appendix A for more details).…”

Section: Materials and Methodsmentioning

confidence: 99%

“…Recent results illustrate that competition for shared cellular resources has profound implications regarding fundamental properties of symmetric genetic switches [ 61 , 62 , 63 ]. Here, we significantly extend these findings to the case of asymmetric toggle switches [ 64 ], thus amplifying the impact of our analysis by considering a much wider and experimentally more realistic set of circuits.…”

Section: Introductionmentioning

confidence: 99%

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Stability and Robustness of Unbalanced Genetic Toggle Switches in the Presence of Scarce Resources

Yong

György

2021

Life

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While the vision of synthetic biology is to create complex genetic systems in a rational fashion, system-level behaviors are often perplexing due to the context-dependent dynamics of modules. One major source of context-dependence emerges due to the limited availability of shared resources, coupling the behavior of disconnected components. Motivated by the ubiquitous role of toggle switches in genetic circuits ranging from controlling cell fate differentiation to optimizing cellular performance, here we reveal how their fundamental dynamic properties are affected by competition for scarce resources. Combining a mechanistic model with nullcline-based stability analysis and potential landscape-based robustness analysis, we uncover not only the detrimental impacts of resource competition, but also how the unbalancedness of the switch further exacerbates them. While in general both of these factors undermine the performance of the switch (by pushing the dynamics toward monostability and increased sensitivity to noise), we also demonstrate that some of the unwanted effects can be alleviated by strategically optimized resource competition. Our results provide explicit guidelines for the context-aware rational design of toggle switches to mitigate our reliance on lengthy and expensive trial-and-error processes, and can be seamlessly integrated into the computer-aided synthesis of complex genetic systems.

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“…For instance, we have already seen that in case of balanced toggle switches (i.e.,

), the dynamics are bistable if

would have the opposite effect, confirmed in Figure 3 b.…”

Section: Resultsmentioning

confidence: 99%

“…To illustrate the detrimental effects of such competition, consider the collective behavior of N toggle switches, given by the dynamics

where

for

Section: Resultsmentioning

confidence: 99%

“…Focusing first on balanced toggle switches (i.e.,

), with

the nullclines

and

intersect three times if

, it pushes the nullclines lower in Figure 1 a, eventually causing the transition from bistability (middle panel in Figure 1 a) to monostability (right panel in Figure 1 a).…”

Section: Materials and Methodsmentioning

confidence: 99%

“…While in the case of balanced toggle switches an equilibrium lies either on the

or on the

manifolds [ 61 ] (middle panel in Figure 1 b), in case of unbalanced switches this is no longer true. In particular, fixed points of ( 6 ) given by the intersections of the nullclines

and

must also satisfy the constraint

as illustrated in the right panel in Figure 1 b (see Appendix A for more details).…”

Section: Materials and Methodsmentioning

confidence: 99%