Mathematical model of GAL regulon dynamics in Saccharomyces cerevisiae
Mathematical model of GAL regulon dynamics in Saccharomyces cerevisiae
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DOI：
10.1016/j.jtbi.2011.10.012
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发表时间：
2012-01-21
影响因子：
2
通讯作者：
Mackey, Michael C.
中科院分区：
文献类型：
--
作者：
Apostu, Raluca;Mackey, Michael C.
基因开关在自然界中普遍存在，并为细胞提供了一种适应不断变化的环境的策略。GAL开关是一个有趣的例子，但并没有被完全理解。GAL开关允许生物体代谢半乳糖，并控制负责半乳糖代谢的机制是开启还是关闭。目前，人们还不清楚半乳糖信号是如何被转录机制感知的。在这里，我们利用定量工具来了解酿酒酵母细胞对半乳糖的反应，并分析其运作的可能分子机制。我们在种群水平上开发了一个基于关键调节蛋白Gal4p、Gal80p和Gal3p相互作用的动态模型。据我们所知，这里提出的模型是第一个定性再现实验中发现的双稳态网络行为的模型。鉴于目前对GAL回路诱导的理解（Wightman et al., 2008; Jiang et al., 2009），我们提出最有可能导致GAL基因转录激活的体内机制是半乳糖激活的Gal3p和GaI80p之间的物理相互作用，复合物Gal3p- gal80p仍然结合在GAL启动子上。我们的数学模型与Acar et al.（2005）的野生型、gal3 Delta和gal80 Delta突变株的流式细胞术图谱一致，并且涉及到与Acar et al.（2010）收集的数据集中具有相同定性特征的活性转录细胞的一小部分。此外，计算模型为独立实验室在处理半乳糖诱导的二元响应与分级响应的实验问题时获得的矛盾结果提供了解释。(C) 2011 Elsevier Ltd.版权所有。
Genetic switches are prevalent in nature and provide cells with a strategy to adapt to changing environments. The GAL switch is an intriguing example which is not understood in all detail. The GAL switch allows organisms to metabolize galactose, and controls whether the machinery responsible for the galactose metabolism is turned on or off. Currently, it is not known exactly how the galactose signal is sensed by the transcriptional machinery. Here we utilize quantitative tools to understand the S. cerevisiae cell response to galactose challenge, and to analyze the plausible molecular mechanisms underlying its operation. We work at a population level to develop a dynamic model based on the interplay of the key regulatory proteins Gal4p, Gal80p, and Gal3p. To our knowledge, the model presented here is the first to reproduce qualitatively the bistable network behavior found experimentally. Given the current understanding of the GAL circuit induction (Wightman et al., 2008: Jiang et al., 2009), we propose that the most likely in vivo mechanism leading to the transcriptional activation of the GAL genes is the physical interaction between galactose-activated Gal3p and GaI80p, with the complex Gal3p-Gal80p remaining bound at the GAL promoters. Our mathematical model is in agreement with the flow cytometry profiles of wild type, gal3 Delta and gal80 Delta mutant strains from Acar et al. (2005), and involves a fraction of actively transcribing cells with the same qualitative features as in the data set collected by Acar et al. (2010). Furthermore, the computational modeling provides an explanation for the contradictory results obtained by independent laboratories when tackling experimentally the issue of binary versus graded response to galactose induction. (C) 2011 Elsevier Ltd. All rights reserved.