The unreasonable effectiveness of equilibrium gene regulation through the cell cycle.

Cell systems Pub Date : 2024-07-17 Epub Date: 2024-07-08 DOI:10.1016/j.cels.2024.06.002
Jose M G Vilar, Leonor Saiz
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Abstract

Systems like the prototypical lac operon can reliably hold repression of transcription upon DNA replication across cell cycles with just 10 repressor molecules per cell and behave as if they were at equilibrium. The origin of this phenomenology is still an unresolved question. Here, we develop a general theory to analyze strong perturbations in quasi-equilibrium systems and use it to quantify the effects of DNA replication in gene regulation. We find a scaling law linking actual with predicted equilibrium transcription via a single kinetic parameter. We show that even the lac operon functions beyond the physical limits of naive regulation through compensatory mechanisms that suppress non-equilibrium effects. Synthetic systems without adjuvant activators, such as the cAMP receptor protein (CRP), lack this reliability. Our results provide a rationale for the function of CRP, beyond just being a tunable activator, as a mitigator of cell cycle perturbations.

Abstract Image

细胞周期中平衡基因调控的不合理有效性。
像典型的lac操作子这样的系统,在DNA复制时,每个细胞只需10个抑制剂分子,就能在整个细胞周期中可靠地保持转录抑制,其表现就像处于平衡状态一样。这种现象的起源仍是一个悬而未决的问题。在这里,我们提出了一种通用理论来分析准平衡系统中的强扰动,并用它来量化 DNA 复制对基因调控的影响。我们发现了一个通过单一动力学参数将实际平衡转录与预测平衡转录联系起来的缩放定律。我们发现,即使是 lac 操作子也能通过补偿机制抑制非均衡效应,从而超越天真调控的物理极限。没有辅助激活剂的合成系统,如 cAMP 受体蛋白(CRP),缺乏这种可靠性。我们的研究结果为 CRP 的功能提供了理论依据,它不仅是一种可调节的激活剂,还是细胞周期扰动的缓解剂。
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