Growth feedback confers cooperativity in resource-competing synthetic gene circuits
Growth feedback confers cooperativity in resource-competing synthetic gene circuits
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DOI：
10.1016/j.chaos.2023.113713
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发表时间：
2023-06-24
影响因子：
7.8
通讯作者：
Tian，Xiao-Jun
中科院分区：
文献类型：
--
作者：
Melendez-Alvarez，Juan Ramon;Zhang，Rong;Tian，Xiao-Jun
模块化是设计合成基因电路的一个关键概念，因为它允许使用特征良好的构建模块构建复杂的分子系统。该领域的主要挑战之一是这些模块化组件在组装成更大的电路时通常无法按预期运行。主要问题之一是由资源竞争引起的，即回路中的多个基因争夺相同的有限细胞资源，例如转录因子和核糖体。此外，合成基因电路和细胞生长之间的相互抑制会导致生长反馈，从而显着影响其宿主电路动态。然而，在资源竞争和生长反馈交织在一起的情况下，基因回路动力学的复杂性尚不完全清楚。这项研究开发了一个理论框架，通过考虑生长反馈和资源竞争来研究合成基因回路的动态。我们的结果表明，在生长反馈下，资源竞争基因回路之间存在合作行为。合作或竞争是由代谢负担阈值非单调决定的。这两种不同的效应可能导致一个电路被另一个电路激活或失活。最后，增长反馈调节的合作性可以减弱赢者通吃的资源竞争。这些发现表明，生长反馈和资源竞争的耦合在宿主电路系统的动态中起着至关重要的作用，了解其影响有助于控制意外的基因表达行为。
Modularity is a key concept in designing synthetic gene circuits, as it allows for constructing complex molecular systems using well-characterized building blocks. One of the major challenges in this field is that these modular components often do not function as expected when assembled into larger circuits. One of the major issues is caused by resource competition, where multiple genes in the circuit compete for the same limited cellular resources, such as transcription factors and ribosomes. In addition, the mutual inhibition between synthetic gene circuits and cell growth results in growth feedback that significantly impacts its host-circuit dynamics. However, the complexity of the gene circuit dynamics under intertwined resource competition and growth feedback is not fully understood. This study developed a theoretical framework to examine the dynamics of synthetic gene circuits by considering both growth feedback and resource competition. Our results suggest a cooperative behavior between resource-competing gene circuits under growth feedback. Cooperation or competition is non-monotonically determined by the metabolic burden threshold. These two diverse effects could lead to the activation or deactivation of one circuit by the other. Lastly, the cooperativity mediated by growth feedback can attenuate the winner-takes-all resource competition. These findings show that coupling growth feedback and resource competition plays a crucial role in the dynamics of the host-circuit system, and understanding its effects helps control unexpected gene expression behaviors.