A model of the cell-autonomous mammalian circadian clock
A model of the cell-autonomous mammalian circadian clock
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DOI：
10.1073/pnas.0904837106
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发表时间：
2009-07-07
影响因子：
11.1
通讯作者：
Doyle, Francis J., III
中科院分区：
文献类型：
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作者：
Mirsky, Henry P.;Liu, Andrew C.;Doyle, Francis J., III
在原核生物和真核生物中，细胞内分子钟的昼夜节律是非常明显的。时钟装置由自动调节反馈环路驱动，这些环路导致组件的最大值彼此之间处于固定相位关系的振荡水平。这些相位关系是表征时钟运行的关键指标。在这项研究中，我们从小鼠细胞内生物钟的调节结构建立了一个数学模型，并使用迭代进化策略确定了它的参数，通过遵守细胞自主振荡器中的相位分离实现了最低成本。根据实验观察到的基因敲除的细胞自主昼夜节律表型，特别是节律性的保持和分子时钟组件表达水平的变化，对该模型进行了评估。这些检验表明，该模型具有良好的从头预测能力。此外，敏感性分析表明，这些基因敲除表型对参数扰动具有很强的鲁棒性。
Circadian timekeeping by intracellular molecular clocks is evident widely in prokaryotes and eukaryotes. The clockworks are driven by autoregulatory feedback loops that lead to oscillating levels of components whose maxima are in fixed phase relationships with one another. These phase relationships are the key metric characterizing the operation of the clocks. In this study, we built a mathematical model from the regulatory structure of the intracellular circadian clock in mice and identified its parameters using an iterative evolutionary strategy, with minimum cost achieved through conformance to phase separations seen in cell-autonomous oscillators. The model was evaluated against the experimentally observed cell-autonomous circadian phenotypes of gene knockouts, particularly retention of rhythmicity and changes in expression level of molecular clock components. These tests reveal excellent de novo predictive ability of the model. Furthermore, sensitivity analysis shows that these knockout phenotypes are robust to parameter perturbation.