Designer gene networks: Towards fundamental cellular control
Designer gene networks: Towards fundamental cellular control
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DOI：
10.1063/1.1345702
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发表时间：
2001-03-01
期刊：
影响因子：
2.9
通讯作者：
Collins, JJ
中科院分区：
文献类型：
--
作者：
Hasty, J;Isaacs, F;Collins, JJ
通过设计合成遗传网络来控制细胞功能的工程学方法正变得越来越合理。在这里，我们将展示如何自然发生的网络可以用作人工网络设计的部件列表，以及模型制定如何导致与非线性动力学和统计物理相关的计算和分析方法。我们首先回顾了合成基因网络的相关工作，突出了关于基因开关和振荡器的重要实验结果。然后，我们提出了一个确定性模型的推导，描述了在一个单基因网络的蛋白质浓度的时间演变。在稳态蛋白质浓度的双稳态自然出现作为自动调节反馈的结果，我们专注于蛋白质浓度作为降解速率的函数的滞后特性。然后，我们制定了与蛋白质降解速率相互作用的外部噪声源的影响。我们通过构建蛋白质开关来证明这种制剂的实用性，由此外部噪声脉冲用于在两个值之间切换蛋白质浓度。在早期工作的领导下，我们展示了如何添加第二个网络组件可以用来构建一个弛张振荡器，从而驱动系统的磁滞回线。我们强调的频率依赖性的可调参数值，并讨论设计的可行性。我们强调如何模型方程可以用来开发鲁棒振荡的设计标准，并说明这一点与参数图照亮给定参数值的振荡区域。然后，我们转向利用一个内在的细胞过程作为控制振荡的手段。我们考虑一个网络设计，表现出自我维持的振荡，并讨论在同步的背景下驱动的振荡器。然后，作为第二个设计，我们考虑一个合成网络的参数值附近，但外面，振荡边界。在这种情况下，我们展示了共振如何导致细胞信号的振荡和放大的诱导。最后，我们构建了一个切换开关，从积极的监管元件，并比较这个网络的开关特性与那些使用负调控构建的网络。我们的研究结果证明了模型分析在构建合成基因调控网络中的实用性。(C)2001年美国物理学会。
The engineered control of cellular function through the design of synthetic genetic networks is becoming plausible. Here we show how a naturally occurring network can be used as a parts list for artificial network design, and how model formulation leads to computational and analytical approaches relevant to nonlinear dynamics and statistical physics. We first review the relevant work on synthetic gene networks, highlighting the important experimental findings with regard to genetic switches and oscillators. We then present the derivation of a deterministic model describing the temporal evolution of the concentration of protein in a single-gene network. Bistability in the steady-state protein concentration arises naturally as a consequence of autoregulatory feedback, and we focus on the hysteretic properties of the protein concentration as a function of the degradation rate. We then formulate the effect of an external noise source which interacts with the protein degradation rate. We demonstrate the utility of such a formulation by constructing a protein switch, whereby external noise pulses are used to switch the protein concentration between two values. Following the lead of earlier work, we show how the addition of a second network component can be used to construct a relaxation oscillator, whereby the system is driven around the hysteresis loop. We highlight the frequency dependence on the tunable parameter values, and discuss design plausibility. We emphasize how the model equations can be used to develop design criteria for robust oscillations, and illustrate this point with parameter plots illuminating the oscillatory regions for given parameter values. We then turn to the utilization of an intrinsic cellular process as a means of controlling the oscillations. We consider a network design which exhibits self-sustained oscillations, and discuss the driving of the oscillator in the context of synchronization. Then, as a second design, we consider a synthetic network with parameter values near, but outside, the oscillatory boundary. In this case, we show how resonance can lead to the induction of oscillations and amplification of a cellular signal. Finally, we construct a toggle switch from positive regulatory elements, and compare the switching properties for this network with those of a network constructed using negative regulation. Our results demonstrate the utility of model analysis in the construction of synthetic gene regulatory networks. (C) 2001 American Institute of Physics.