Design of Oscillatory Networks through Post-Translational Control of Network Components
Design of Oscillatory Networks through Post-Translational Control of Network Components
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DOI：
10.35534/sbe.2023.10004
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发表时间：
2023-03
期刊：
影响因子：
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通讯作者：
Brianna Jayanthi;S. Jayanthi;Laura Segatori
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文献类型：
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作者：
Brianna Jayanthi;S. Jayanthi;Laura Segatori
生物系统中的许多基本功能，包括细胞周期进程和昼夜节律调节，都由特定分子的周期性行为所控制。这些周期性行为源于生物分子网络中产生振荡输出信号的组件的精确排列。这些网络的各个组成部分的动态特性，如成熟延迟和退化率，通常在确定网络的振荡行为中起着关键作用。在这项研究中，我们探讨了网络组件的翻译后调制作为一种手段，以产生具有振荡行为的遗传电路和扰动的振荡功能。具体来说，我们使用NanoDeg平台-由靶向特异性纳米抗体和降解决定子标签组成的双功能分子-来控制电路组件的降解速率，并预测NanoDeg介导的关键电路组件的翻译后耗尽对一系列原始振荡网络拓扑结构的行为的影响。我们模拟了两种主要类型的振荡器的行为，即弛豫振荡器拓扑结构（激活抑制器和古德温振荡器）和环形振荡器拓扑结构（represilators）。我们确定了两个主要的机制，非振荡网络可以诱导振荡，通过翻译后调制的网络组件：增加网络组件的时间尺度的分离和减轻泄漏的网络组件的表达。这些结果与以前的研究结果描述的效果的时间尺度分离和缓解泄漏的表达振荡行为。因此，这项工作验证了使用工具来控制蛋白质降解速率作为一种策略来调节现有的振荡信号和构建振荡网络。此外，这项研究提供了设计规则，以实现这种基于使用NanoDeg平台控制蛋白质降解速率的方法，该平台不需要对网络组件进行遗传操作，并且可以适应几乎任何细胞蛋白质。这项工作还建立了一个框架，探索使用工具的生物分子网络的翻译后扰动，并产生所需的行为的网络输出。
Many essential functions in biological systems, including cell cycle progression and circadian rhythm regulation, are governed by the periodic behaviors of specific molecules. These periodic behaviors arise from the precise arrangement of components in biomolecular networks that generate oscillatory output signals. The dynamic properties of individual components of these networks, such as maturation delays and degradation rates, often play a key role in determining the network’s oscillatory behavior. In this study, we explored the post-translational modulation of network components as a means to generate genetic circuits with oscillatory behaviors and perturb the oscillation features. Specifically, we used the NanoDeg platform—A bifunctional molecule consisting of a target-specific nanobody and a degron tag—to control the degradation rates of the circuit’s components and predicted the effect of NanoDeg-mediated post-translational depletion of a key circuit component on the behavior of a series of proto-oscillating network topologies. We modeled the behavior of two main classes of oscillators, namely relaxation oscillator topologies (the activator-repressor and the Goodwin oscillator) and ring oscillator topologies (repressilators). We identified two main mechanisms by which non-oscillating networks could be induced to oscillate through post-translational modulation of network components: an increase in the separation of timescales of network components and mitigation of the leaky expression of network components. These results are in agreement with previous findings describing the effect of timescale separation and mitigation of leaky expression on oscillatory behaviors. This work thus validates the use of tools to control protein degradation rates as a strategy to modulate existing oscillatory signals and construct oscillatory networks. In addition, this study provides the design rules to implement such an approach based on the control of protein degradation rates using the NanoDeg platform, which does not require genetic manipulation of the network components and can be adapted to virtually any cellular protein. This work also establishes a framework to explore the use of tools for post-translational perturbations of biomolecular networks and generates desired behaviors of the network output.