Bimodal gene expression in noncooperative regulatory systems
Bimodal gene expression in noncooperative regulatory systems
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DOI：
10.1073/pnas.1008965107
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发表时间：
2010-12-21
影响因子：
11.1
通讯作者：
Tabaka, Marcin
中科院分区：
文献类型：
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作者：
Ochab-Marcinek, Anna;Tabaka, Marcin
基因表达的双峰性作为一种促进表型多样性的机制，提高了细胞在波动环境中的生存能力。到目前为止，基因调控系统的双峰反应被归因于转录因子结合或反馈环的协同作用。目前还不清楚转录因子的非合作结合是否会在开环系统中引起双峰现象。我们研究了两步级联(确定性的单稳态系统)中基因表达的理论模型，在该模型中，调控基因产生对目标基因的活性具有非线性影响的转录因子。我们证明了转录因子在细胞群体中的单峰分布可以在没有合作转录因子结合的情况下产生双峰稳态输出。我们介绍了一种简单的几何构造方法，它允许人们预测双峰的开始。该构建只涉及调控基因的爆发参数和靶基因的剂量-反应曲线。利用这种方法，我们证明了当诱导物或辅阻遏物的浓度不同时，基因表达可能在单峰和双峰之间切换。这些发现可以解释实验中观察到的由四环素抑制物控制的荧光蛋白报告组成的级联的双峰反应。几何结构为设计实验和解释实验结果提供了有用的工具。我们的发现可能对理解细胞群体在不断变化的环境中生存所采取的策略具有重要意义。
Bimodality of gene expression, as a mechanism contributing to phenotypic diversity, enhances the survival of cells in a fluctuating environment. To date, the bimodal response of a gene regulatory system has been attributed to the cooperativity of transcription factor binding or to feedback loops. It has remained unclear whether noncooperative binding of transcription factors can give rise to bimodality in an open-loop system. We study a theoretical model of gene expression in a two-step cascade (a deterministically monostable system) in which the regulatory gene produces transcription factors that have a nonlinear effect on the activity of the target gene. We show that a unimodal distribution of transcription factors over the cell population can generate a bimodal steady-state output without cooperative transcription factor binding. We introduce a simple method of geometric construction that allows one to predict the onset of bimodality. The construction only involves the parameters of bursting of the regulatory gene and the dose-response curve of the target gene. Using this method, we show that the gene expression may switch between unimodal and bimodal as the concentration of inducers or corepressors is varied. These findings may explain the experimentally observed bimodal response of cascades consisting of a fluorescent protein reporter controlled by the tetracycline repressor. The geometric construction provides a useful tool for designing experiments and for interpretation of their results. Our findings may have important implications for understanding the strategies adopted by cell populations to survive in changing environments.