Comprehensive modelling of the Neurospora circadian clock and its temperature compensation.
Comprehensive modelling of the Neurospora circadian clock and its temperature compensation.
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DOI：
10.1371/journal.pcbi.1002437
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发表时间：
2012
影响因子：
4.3
通讯作者：
Schwartz JM
中科院分区：
文献类型：
--
作者：
Tseng YY;Hunt SM;Heintzen C;Crosthwaite SK;Schwartz JM
生物钟提供外部时间的内部测量，使生物体能够预测和利用环境中可预测的日常变化。由生物钟驱动的节律具有大约24小时的温度补偿周期性，其在恒定条件下持续存在，并且可以通过环境时间线索重置。计算建模有助于我们理解生物钟的分子机制，然而，将大量的时钟组件及其相互作用整合到一个能够解释时钟表型全部宽度的单一综合模型中仍然是一个重大挑战。在这里，我们提出了一个全面的动力学模型的粗糙脉孢菌的昼夜节律钟，包括其关键组成部分和它们的转录和转录后调控。该模型考虑了广泛的时钟特性，包括：21.6小时的周期性，在恒定条件下的持续振荡，在恒定光下的重复性，通过短暂的光脉冲重置，以及夹带到全光周期。通过控制分析确定了影响振荡周期和振幅的关键部件。此外，模拟使我们能够提出一种温度补偿机制，该机制是通过同时增加frq RNA的翻译和减少FRQ蛋白的核输入来实现的。生物钟是一种内部计时器，它整合来自环境的信号，并协调细胞事件在一天中最有利的时间发生。动物、植物、真菌和细菌的生物钟具有相似的特征和分子结构。它们的周期约为24小时，在恒定的条件下持续存在，并可以通过环境时间线索（如光线和温度）重置。另一个基本性质，其分子基础知之甚少，是周期是温度补偿的，即它在一定温度范围内保持不变。计算建模已经成为预测和理解这种复杂分子系统的潜在机制的有价值的工具，但现有的时钟模型通常局限于它们所覆盖的分子反应的范围和它们能够再现的条件的广度。因此，我们建立了一个全面的模型的生物钟的真菌粗糙脉孢菌，其中包括现有的知识的生物化学脉孢菌时钟。我们验证了这个模型对广泛的实验表型，然后使用该模型来研究温度补偿的可能的分子解释。我们的模拟表明，温度补偿周期是通过改变一个关键时钟蛋白的丰度和细胞定位来实现的。
Circadian clocks provide an internal measure of external time allowing organisms to anticipate and exploit predictable daily changes in the environment. Rhythms driven by circadian clocks have a temperature compensated periodicity of approximately 24 hours that persists in constant conditions and can be reset by environmental time cues. Computational modelling has aided our understanding of the molecular mechanisms of circadian clocks, nevertheless it remains a major challenge to integrate the large number of clock components and their interactions into a single, comprehensive model that is able to account for the full breadth of clock phenotypes. Here we present a comprehensive dynamic model of the Neurospora crassa circadian clock that incorporates its key components and their transcriptional and post-transcriptional regulation. The model accounts for a wide range of clock characteristics including: a periodicity of 21.6 hours, persistent oscillation in constant conditions, arrhythmicity in constant light, resetting by brief light pulses, and entrainment to full photoperiods. Crucial components influencing the period and amplitude of oscillations were identified by control analysis. Furthermore, simulations enabled us to propose a mechanism for temperature compensation, which is achieved by simultaneously increasing the translation of frq RNA and decreasing the nuclear import of FRQ protein. Circadian clocks are internal timekeepers that integrate signals from the environment and orchestrate cellular events to occur at the most favourable time of day. Circadian clocks in animals, plants, fungi and bacteria have similar characteristic properties and molecular architecture. They have a periodicity of approximately 24 hours, persist in constant conditions and can be reset by environmental time cues such as light and temperature. Another essential property, whose molecular basis is poorly understood, is that the period is temperature compensated i.e. it remains the same over a range of temperatures. Computational modelling has become a valuable tool to predict and understand the underlying mechanisms of such complex molecular systems, but existing clock models are often restricted in the scope of molecular reactions they cover and in the breadth of conditions they are able to reproduce. We therefore built a comprehensive model of the circadian clock of the fungus Neurospora crassa, which encompasses existing knowledge of the biochemistry of the Neurospora clock. We validated this model against a wide range of experimental phenotypes and then used the model to investigate possible molecular explanations of temperature compensation. Our simulations suggest that temperature compensation of period is achieved by changing the abundance and cellular localisation of a key clock protein.
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