Simplified mechanistic models of gene regulation for analysis and design.
Simplified mechanistic models of gene regulation for analysis and design.
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DOI：
10.1098/rsif.2015.0312
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发表时间：
2015-07-06
期刊：
影响因子：
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通讯作者：
Papachristodoulou A
中科院分区：
文献类型：
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作者：
Hancock EJ;Stan GB;Arpino JA;Papachristodoulou A
基因调控的简化机制模型是系统生物学的基础，也是合成生物学的关键。然而，传统的简化模型通常具有不可直接测量的输出，并且基于在实验条件下通常不成立的假设。为了解决这些问题，我们提出了一种“模型简化”的方法，并简化了总mRNA和总蛋白浓度的动力学模型，将测量、模型和生化机制联系起来。建议的方法是基于普遍适用的假设，并包括常规模型不适用的系统和合成生物学中的典型案例。我们使用了关于“反应速度”的新假设，这是方法学与实验数据保持一致所必需的。我们还应用该方法在存在多个蛋白质结合位点的情况下提出了基因调控的简化模型，提供了生物学见解和对该方法的一般性的说明。最后，我们展示了总蛋白浓度的建模使我们能够解决关于基因调控的关键问题，例如效率、负担、竞争和模块化。
Simplified mechanistic models of gene regulation are fundamental to systems biology and essential for synthetic biology. However, conventional simplified models typically have outputs that are not directly measurable and are based on assumptions that do not often hold under experimental conditions. To resolve these issues, we propose a ‘model reduction’ methodology and simplified kinetic models of total mRNA and total protein concentration, which link measurements, models and biochemical mechanisms. The proposed approach is based on assumptions that hold generally and include typical cases in systems and synthetic biology where conventional models do not hold. We use novel assumptions regarding the ‘speed of reactions’, which are required for the methodology to be consistent with experimental data. We also apply the methodology to propose simplified models of gene regulation in the presence of multiple protein binding sites, providing both biological insights and an illustration of the generality of the methodology. Lastly, we show that modelling total protein concentration allows us to address key questions on gene regulation, such as efficiency, burden, competition and modularity.