Emergent Damped Oscillation Induced by Nutrient-Modulating Growth Feedback
Emergent Damped Oscillation Induced by Nutrient-Modulating Growth Feedback
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DOI：
10.1021/acssynbio.1c00041
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发表时间：
2021-04-29
影响因子：
4.7
通讯作者：
Tian, Xiao-Jun
中科院分区：
文献类型：
--
作者：
Melendez-Alvarez, Juan;He, Changhan;Tian, Xiao-Jun
生长反馈是合成基因电路与宿主细胞生长之间的内在耦合，可以显著改变电路的行为。以前，各种各样的涌现行为，如增长双稳态，增强超灵敏度，和拓扑依赖性记忆丧失，据报道是由生长反馈诱导。然而，生长反馈对电路功能的影响仍有待研究。在这里，我们报告了一个意想不到的阻尼振荡行为的自激活基因回路诱导的营养调节生长反馈。具体而言，在将激活的自激活开关稀释到具有适度营养的新鲜培养基中后，其基因表达首先随着细胞生长而降低，然后在其达到稳态之前显示出显著的过冲，从而导致阻尼振荡动力学。用粗粒度模型拟合数据表明，基因生产率的非单调增长率调节。振荡的潜在机制是通过分子数学模型来证明的，该模型包括核糖体向基因产生、细胞生长和细胞维持的分配。有趣的是，该模型预测了振荡幅度对营养水平的反直觉依赖性，其中在中等营养物质的培养基中发现了最高峰，但在富含营养物质的培养基中没有观察到。我们通过调整培养基中的营养水平，实验验证了这一预测。我们没有观察到显着的拨动开关的振荡行为，这表明阻尼振荡行为的出现取决于电路网络拓扑结构。我们的研究结果表明，一个新的非线性涌现行为介导的生长反馈，这取决于核糖体之间的基因电路和细胞生长的分配。
Growth feedback, the inherent coupling between the synthetic gene circuit and the host cell growth, could significantly change the circuit behaviors. Previously, a diverse array of emergent behaviors, such as growth bistability, enhanced ultrasensitivity, and topology-dependent memory loss, were reported to be induced by growth feedback. However, the influence of the growth feedback on the circuit functions remains underexplored. Here, we reported an unexpected damped oscillatory behavior of a self-activation gene circuit induced by nutrient-modulating growth feedback. Specifically, after dilution of the activated self-activation switch into the fresh medium with moderate nutrients, its gene expression first decreases as the cell grows and then shows a significant overshoot before it reaches the steady state, leading to damped oscillation dynamics. Fitting the data with a coarse-grained model suggests a nonmonotonic growth-rate regulation on gene production rate. The underlying mechanism of the oscillation was demonstrated by a molecular mathematical model, which includes the ribosome allocation toward gene production, cell growth, and cell maintenance. Interestingly, the model predicted a counterintuitive dependence of oscillation amplitude on the nutrition level, where the highest peak was found in the medium with moderate nutrients, but was not observed in rich nutrients. We experimentally verified this prediction by tuning the nutrient level in the culture medium. We did not observe significant oscillatory behavior for the toggle switch, suggesting that the emergence of damped oscillatory behavior depends on circuit network topology. Our results demonstrated a new nonlinear emergent behavior mediated by growth feedback, which depends on the ribosome allocation between gene circuit and cell growth.