Computational study on ratio-sensing in yeast galactose utilization pathway.
Computational study on ratio-sensing in yeast galactose utilization pathway.
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酵母半乳糖利用途径中比率传感的计算研究。
DOI：
10.1371/journal.pcbi.1007960
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发表时间：
2020-12
影响因子：
4.3
通讯作者：
Tang C
中科院分区：
文献类型：
--
作者：
Hong J;Hua B;Springer M;Tang C
代谢网络根据外部营养信号进行基因表达调节。在微生物中，用于运输和分解代谢不太优选的碳源的酶的合成在优选碳源的存在下受到抑制。对于大多数微生物来说，葡萄糖是首选的碳源，长期以来人们一直认为，只要环境中存在葡萄糖，由于分解代谢物的抑制，与替代碳源代谢相关的基因的表达就会被关闭。然而，最近的研究表明，半乳糖（GAL）代谢网络的诱导并不仅仅取决于葡萄糖的消耗。相反，GAL 基因对半乳糖与葡萄糖的外部浓度比做出反应，这是一种未知机制的现象，我们称之为比率传感。使用数学模型，我们发现比率传感是一种普遍现象，可能由两个碳源之间共享转运蛋白的竞争、转录因子之间用于与靶基因的公共调控序列结合的竞争或上述两个竞争水平的组合而产生。我们分析了描述竞争相互作用的参数如何影响每种情况下的比率传感行为，并发现两层信号集成的串联可以扩大比率传感的动态范围。最后，我们研究了电路拓扑对比率传感的影响，发现将负自动调节和/或相干前馈环路图案合并到基本信号积分单元中可以调整对外部营养信号响应的灵敏度。我们的研究不仅加深了我们对酵母 GAL 代谢调节中如何实现比率传感的理解，而且阐明了可用于其他生物环境的比率传感信号处理的设计原理，例如引入到合成生物学应用的电路设计中。微生物根据其环境中可用的营养选择的多样性，对营养的吸收和代谢做出复杂的选择。在经过充分研究的酵母半乳糖利用网络中，最近的一项研究表明，半乳糖代谢基因对半乳糖与葡萄糖的外部浓度比做出反应。使用计算模型，我们表明这种现象可能是由半乳糖和葡萄糖之间对转运蛋白的竞争、转录因子之间对启动子的竞争或这两种机制的组合引起的。我们进一步揭示了控制参数，这些参数决定了系统对竞争输入信号的敏感性，并决定了在每种情况下诱导代谢网络所需的浓度比。将转运蛋白水平和转录水平的竞争抑制相结合可以扩大比率传感机制，从而产生强大的信号整合模块。我们怀疑此类模块可能在生物学的许多领域中很常见。
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 could 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 could 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. Microbes make sophisticated choices about the uptake and metabolism of nutrients depending on the variety of nutrient choices available to them in their environment. In the well-studied yeast galactose utilization network, a recent study has shown that galactose metabolic genes respond to the external concentration ratio of galactose to glucose. Using computational models, we showed that this type of phenomenon could arise from a competition between galactose and glucose for transporters, a competition between transcription factors for promoters, or a combination of these two mechanisms. We further revealed the controlling parameters that determined the system sensitivity towards competing input signals and that determined the concentration ratio required to induce the metabolic network in each scenario. Combining competition inhibition at both the transporter level and the transcriptional level can enlarge the ratio-sensing regime, resulting a robust signal integration module. We suspect that modules of this kind may be common in many areas of biology.
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影响因子：
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