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Coupling between feedback loops in autoregulatory networks affects bistability range, open-loop gain and switching times

机译:自动调节网络中反馈回路之间的耦合会影响双稳态范围,开环增益和切换时间

摘要

Biochemical regulatory networks governing diverse cellular processes such as stress-response,differentiation and cell cycle often contain coupled feedback loops. We aim at understandinghow features of feedback architecture, such as the number of loops, the sign of the loops andthe type of their coupling, affect network dynamical performance. Specifically, we investigatehow bistability range, maximum open-loop gain and switching times of a network withtranscriptional positive feedback are affected by additive or multiplicative coupling withanother positive- or negative-feedback loop. We show that a network's bistability range ispositively correlated with its maximum open-loop gain and that both quantities depend on thesign of the feedback loops and the type of feedback coupling. Moreover, we find that theaddition of positive feedback could decrease the bistability range if we control the basal levelin the signal-response curves of the two systems. Furthermore, the addition of negativefeedback has the capacity to increase the bistability range if its dissociation constant is muchlower than that of the positive feedback. We also find that the addition of a positive feedback toa bistable network increases the robustness of its bistability range, whereas the addition of anegative feedback decreases it. Finally, we show that the switching time for a transition from ahigh to a low steady state increases with the effective fold change in gene regulation. Insummary, we show that the effect of coupled feedback loops on the bistability range andswitching times depends on the underlying mechanistic details.
机译:控制各种细胞过程(如应激反应,分化和细胞周期)的生化调节网络通常包含耦合的反馈回路。我们旨在了解反馈体系结构的功能,例如环路的数量,环路的符号及其耦合的类型如何影响网络动态性能。具体来说,我们研究了具有转录正反馈的网络的双稳态范围,最大开环增益和切换时间如何受到与另一个正反馈或负反馈环路的加性或乘性耦合的影响。我们表明,网络的双稳态范围与其最大的开环增益呈正相关,并且两个量都取决于反馈环路的符号和反馈耦合的类型。此外,我们发现,如果我们控制两个系统的信号响应曲线中的基础水平,则增加正反馈会降低双稳态范围。此外,如果负反馈的解离常数比正反馈的解离常数低得多,则添加负反馈具有增加双稳态范围的能力。我们还发现,向双稳态网络添加正反馈会增加其双稳态范围的鲁棒性,而向负反馈添加会降低双稳态网络的稳健性。最后,我们表明从高稳态到低稳态的转换时间随着基因调控的有效倍数变化而增加。总之,我们表明耦合反馈回路对双稳态范围和切换时间的影响取决于潜在的机械细节。

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