Persson Sebastian, Welkenhuysen Niek, Shashkova Sviatlana, Cvijovic Marija
Department of Mathematical Sciences, University of Gothenburg, Gothenburg, Sweden.
Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden.
Front Physiol. 2020 Aug 14;11:954. doi: 10.3389/fphys.2020.00954. eCollection 2020.
Nutrient sensing pathways are playing an important role in cellular response to different energy levels. In budding yeast, , the sucrose non-fermenting protein kinase complex SNF1 is a master regulator of energy homeostasis. It is affected by multiple inputs, among which energy levels is the most prominent. Cells which are exposed to a switch in carbon source availability display a change in the gene expression machinery. It has been shown that the magnitude of the change varies from cell to cell. In a glucose rich environment Snf1/Mig1 pathway represses the expression of its downstream target, such as . However, upon glucose depletion SNF1 is activated which leads to an increase in expression. Our single cell experiments indicate that upon starvation, gene expression pattern of shows rapid increase followed by a decrease to initial state with high cell-to-cell variability. The mechanism behind this behavior is currently unknown. In this work we study the long-term behavior of the Snf1/Mig1 pathway upon glucose starvation with a microfluidics and non-linear mixed effect modeling approach. We show a negative feedback mechanism, involving Snf1 and Reg1, which reduces expression after the initial strong activation. Snf1 kinase activity plays a key role in this feedback mechanism. Our systems biology approach proposes a negative feedback mechanism that works through the SNF1 complex and is controlled by energy levels. We further show that Reg1 likely is involved in the negative feedback mechanism.
营养感应通路在细胞对不同能量水平的反应中发挥着重要作用。在芽殖酵母中，蔗糖非发酵蛋白激酶复合物SNF1是能量稳态的主要调节因子。它受到多种输入的影响，其中能量水平最为突出。暴露于碳源可用性切换的细胞会在基因表达机制上表现出变化。已经表明，这种变化的程度因细胞而异。在富含葡萄糖的环境中，Snf1/Mig1通路会抑制其下游靶标的表达，例如……。然而，在葡萄糖耗尽时，SNF1被激活，这导致……表达增加。我们的单细胞实验表明，饥饿时，……的基因表达模式显示出快速增加，随后下降到初始状态，细胞间差异很大。这种行为背后的机制目前尚不清楚。在这项工作中，我们使用微流控和非线性混合效应建模方法研究了葡萄糖饥饿时Snf1/Mig1通路的长期行为。我们展示了一种负反馈机制，涉及Snf1和Reg1，它在最初的强烈激活后会降低……表达。Snf1激酶活性在这种反馈机制中起关键作用。我们的系统生物学方法提出了一种通过SNF1复合物起作用并受能量水平控制的负反馈机制。我们进一步表明，Reg1可能参与了负反馈机制。
