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Counter-intuitive stochastic behavior of simple gene circuits with negative feedback.

机译:具有负反馈的简单基因电路的违反直觉的随机行为。

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摘要

It has often been taken for granted that negative feedback loops in gene regulation work as homeostatic control mechanisms. If one increases the regulation strength a less noisy signal is to be expected. However, recent theoretical studies have reported the exact contrary, counter-intuitive observation, which has left a question mark over the relationship between negative feedback loops and noise. We explore and systematically analyze several minimal models of gene regulation, where a transcriptional repressor negatively regulates its own expression. For models including a quasi-steady-state assumption, we identify processes that buffer noise change (RNA polymerase binding) or accentuate it (repressor dimerization) alongside increasing feedback strength. Moreover, we show that lumping together transcription and translation in simplified models clearly underestimates the impact of negative feedback strength on the system's noise. In contrast, in systems without a quasi-steady-state assumption, noise always increases with negative feedback strength. Hence, subtle mathematical properties and model assumptions yield different types of noise profiles and, by consequence, previous studies have simultaneously reported decrease, increase or persistence of noise levels with increasing feedback. We discuss our findings in terms of separation of timescales and time correlations between molecular species distributions, extending current theoretical findings on the topic and allowing us to propose what we believe new ways to better characterize noise.
机译:人们通常认为基因调节中的负反馈回路起着稳态控制机制的作用。如果增加调节强度,则可以预期到噪声较小的信号。但是,最近的理论研究报告了完全相反的,违反直觉的观察,这给负反馈回路与噪声之间的关系留下了疑问。我们探索和系统分析基因调控的几个最小模型,其中转录阻遏物负面调节其自身的表达。对于包括准稳态假设的模型,我们确定了在增加反馈强度的同时缓冲噪声变化(RNA聚合酶结合)或加重噪声变化(阻遏物二聚化)的过程。此外,我们表明,将简化模型中的转录和翻译集中在一起,显然会低估负反馈强度对系统噪声的影响。相反,在没有准稳态假设的系统中,噪声总是随着负反馈强度而增加。因此,微妙的数学特性和模型假设会产生不同类型的噪声曲线,因此,先前的研究同时报告了随着反馈的增加噪声水平的降低,升高或持续存在。我们根据时间尺度的分离和分子种类分布之间的时间相关性来讨论我们的发现,扩展有关该主题的当前理论发现,并允许我们提出我们认为更好地表征噪声的新方法。

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