School of Chemistry, University of Hyderabad, Central University P.O., Hyderabad, 500046, Telangana, India.
ACS Synth Biol. 2021 Nov 19;10(11):3117-3128. doi: 10.1021/acssynbio.1c00373. Epub 2021 Oct 25.
Bistability is intrinsically connected to various decision making processes in living systems. The operating principles of a bistable switch, generated from a positive feedback loop, are well understood both in natural and synthetic settings. However, the fate of dynamic modularity of a positive feedback loop is unknown when it is connected to another dynamically modular signaling motif. In order to address this, here we investigate feed-forward signaling of a positive feedback loop to determine the fate of a bistable switch under such signaling. Using the potential energy based high-throughput bifurcation analysis method, we uncover that in addition to the conventional bistability the hybrid motifs generate various emergent bistable switches, namely mushroom and isola switches, which are not produced by the individual motifs. Using random parameter sampling, network perturbation, and phase plane analysis, we establish the design principles of such emergent behaviors. Incoherent feed-forward signaling of a positive feedback loop with distinct regulatory thresholds of the two arms of the feed-forward loop are the key requirements for such emergent behaviors. Our calculations show that the specific types of atypical bistable responses depend on the logic gate configuration of the signals. However, the emergent bistable behaviors of the hybrid networks do not depend on the nature of the positive feedback loop.
双稳性与生命系统中的各种决策过程有着内在的联系。在自然和合成环境中，基于正反馈回路产生的双稳开关的工作原理都得到了很好的理解。然而，当正反馈回路与另一个动态模块化信号基序连接时，其动态模块化的命运是未知的。为了解决这个问题，我们在这里研究正反馈回路的前馈信号，以确定在这种信号下双稳开关的命运。我们使用基于势能的高通量分岔分析方法，揭示了除了传统的双稳性外，混合基序还会产生各种新的双稳开关，即蘑菇开关和等离开关，而这些开关是单个基序无法产生的。通过随机参数采样、网络扰动和相平面分析，我们建立了这些涌现行为的设计原则。前馈回路的非相干前馈信号，以及前馈回路两个臂的不同调节阈值，是产生这种涌现行为的关键要求。我们的计算表明，非典型双稳响应的具体类型取决于信号的逻辑门配置。然而，混合网络的涌现双稳行为并不取决于正反馈回路的性质。
