Sainsbury Laboratory, University of Cambridge, Cambridge, United Kingdom.
PLoS Comput Biol. 2023 Aug 4;19(8):e1011265. doi: 10.1371/journal.pcbi.1011265. eCollection 2023 Aug.
Single-cell approaches are revealing a high degree of heterogeneity, or noise, in gene expression in isogenic bacteria. How gene circuits modulate this noise in gene expression to generate robust output dynamics is unclear. Here we use the Bacillus subtilis alternative sigma factor σB as a model system for understanding the role of noise in generating circuit output dynamics. σB controls the general stress response in B. subtilis and is activated by a range of energy and environmental stresses. Recent single-cell studies have revealed that the circuit can generate two distinct outputs, stochastic pulsing and a single pulse response, but the conditions under which each response is generated are under debate. We implement a stochastic mathematical model of the σB circuit to investigate this and find that the system's core circuit can generate both response types. This is despite one response (stochastic pulsing) being stochastic in nature, and the other (single response pulse) being deterministic. We demonstrate that the main determinant for whichever response is generated is the degree with which the input pathway activates the core circuit, although the noise properties of the input pathway also biases the system towards one or the other type of output. Thus, our work shows how stochastic modelling can reveal the mechanisms behind non-intuitive gene circuit output dynamics.
单细胞方法揭示了同基因细菌中基因表达的高度异质性或噪声。基因回路如何调节基因表达中的这种噪声以产生稳健的输出动力学尚不清楚。在这里，我们使用枯草芽孢杆菌替代σ因子σB 作为模型系统来理解噪声在产生电路输出动力学中的作用。σB 控制枯草芽孢杆菌的一般应激反应，并被一系列能量和环境应激激活。最近的单细胞研究表明，该电路可以产生两种不同的输出，随机脉冲和单个脉冲响应，但产生每种响应的条件仍存在争议。我们实现了一个σB 电路的随机数学模型来研究这一点，发现该系统的核心电路可以产生这两种响应类型。尽管一种响应（随机脉冲）本质上是随机的，而另一种响应（单脉冲响应）是确定性的。我们证明，产生哪种响应的主要决定因素是输入途径激活核心电路的程度，尽管输入途径的噪声特性也会使系统偏向于一种或另一种输出类型。因此，我们的工作表明，随机模型如何揭示非直观基因电路输出动力学背后的机制。
