Metabolic networks undergo gene expression regulation in response to external nutrient signals. In microbes, the synthesis of enzymes that are used to transport and catabolize less preferred carbon sources is repressed in the presence of a preferred carbon source. For most microbes, glucose is a preferred carbon source, and it has long been believed that as long as glucose is present in the environment, the expression of genes related to the metabolism of alternative carbon sources is shut down, due to catabolite repression. However, recent studies have shown that the induction of the galactose (GAL) metabolic network does not solely depend on the exhaustion of glucose. Instead, the GAL genes respond to the external concentration ratio of galactose to glucose, a phenomenon of unknown mechanism that we termed ratio-sensing. Using mathematical modeling, we found that ratio-sensing is a general phenomenon that can arise from competition between two carbon sources for shared transporters, between transcription factors for binding to communal regulatory sequences of the target genes, or a combination of the aforementioned two levels of competition. We analyzed how the parameters describing the competitive interaction influenced ratio-sensing behaviors in each scenario and found that the concatenation of both layers of signal integration can expand the dynamical range of ratio-sensing. Finally, we investigated the influence of circuit topology on ratio-sensing and found that incorporating negative auto-regulation and/or coherent feedforward loop motifs to the basic signal integration unit can tune the sensitivity of the response to the external nutrient signals. Our study not only deepened our understanding of how ratio-sensing is achieved in yeast GAL metabolic regulation, but also elucidated design principles for ratio-sensing signal processing that can be used in other biological settings, such as being introduced into circuit designs for synthetic biology applications.

中文翻译：

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酵母半乳糖利用途径中比例感应的计算研究

代谢网络响应外部营养信号而进行基因表达调控。在微生物中，用于运输和分解不太优选的碳源的酶的合成在优选的碳源的存在下被抑制。对于大多数微生物来说，葡萄糖是优选的碳源，并且长期以来人们一直认为，只要葡萄糖存在于环境中，由于分解代谢物的抑制，与替代碳源的代谢相关的基因的表达就会被关闭。但是，最近的研究表明，半乳糖（GAL）代谢网络的诱导并不仅取决于葡萄糖的消耗。取而代之的是，GAL基因响应于半乳糖与葡萄糖的外部浓度比，这是一种未知机制的现象，我们称之为比率感应。使用数学模型，我们发现比率感测是一种普遍现象，可能是由于两个碳源之间对于共享转运蛋白的竞争，与目标基因的公共调控序列结合的转录因子之间的竞争，或者是上述两个水平的结合所致。竞争。我们分析了描述竞争性相互作用的参数如何在每种情况下影响比率感应行为，发现信号整合的两层串联可以扩大比率感应的动态范围。最后，我们研究了电路拓扑结构对比率传感的影响，发现将负自动调节和/或相干前馈环路基元并入基本信号积分单元可以调整对外部营养信号响应的敏感性。