School of Mathematics & Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom.
Department of Mathematics, Faculty of Mathematics and Natural Sciences, University of Bergen, Bergen, Norway.
Sci Rep. 2019 Dec 27;9(1):20196. doi: 10.1038/s41598-019-56587-5.
Cells generate phenotypic diversity both during development and in response to stressful and changing environments, aiding survival. Functionally vital cell fate decisions from a range of phenotypic choices are made by regulatory networks, the dynamics of which rely on gene expression and hence depend on the cellular energy budget (and particularly ATP levels). However, despite pronounced cell-to-cell ATP differences observed across biological systems, the influence of energy availability on regulatory network dynamics is often overlooked as a cellular decision-making modulator, limiting our knowledge of how energy budgets affect cell behaviour. Here, we consider a mathematical model of a highly generalisable, ATP-dependent, decision-making regulatory network, and show that cell-to-cell ATP variability changes the sets of decisions a cell can make. Our model shows that increasing intracellular energy levels can increase the number of supported stable phenotypes, corresponding to increased decision-making capacity. Model cells with sub-threshold intracellular energy are limited to a singular phenotype, forcing the adoption of a specific cell fate. We suggest that energetic differences between cells may be an important consideration to help explain observed variability in cellular decision-making across biological systems.
细胞在发育过程中以及应对压力和不断变化的环境时会产生表型多样性，从而帮助其生存。通过调控网络做出了一系列从各种表型选择中具有重要功能的关键命运决策，其动态依赖于基因表达，因此取决于细胞的能量预算（尤其是 ATP 水平）。然而，尽管在整个生物系统中观察到明显的细胞间 ATP 差异，但能量可用性对调控网络动态的影响往往被忽视为细胞决策的调节剂，这限制了我们对能量预算如何影响细胞行为的认识。在这里，我们考虑了一个高度通用的、依赖于 ATP 的决策调控网络的数学模型，并表明细胞间的 ATP 变异性改变了细胞可以做出的决策集。我们的模型表明，增加细胞内的能量水平可以增加支持的稳定表型数量，从而增加决策能力。细胞内能量低于阈值的模型细胞只能产生一种单一的表型，迫使它们采用特定的细胞命运。我们认为，细胞间的能量差异可能是一个重要的考虑因素，可以帮助解释在整个生物系统中观察到的细胞决策的可变性。
