Understanding environmental adaptation of the fungal circadian clock with mathematical modeling.
Understanding environmental adaptation of the fungal circadian clock with mathematical modeling.
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通过数学建模了解真菌生物钟的环境适应。
DOI：
10.1016/j.bpj.2015.02.025
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发表时间：
2015
影响因子：
3.4
通讯作者：
Henson,MichaelA
中科院分区：
文献类型：
--
作者：
Henson,MichaelA
生物钟产生24小时的节律，为各种生物体中的各种生理和行为过程提供强大的调节，包括真菌脉孢菌属，植物拟南芥属，果蝇和哺乳动物。虽然每个生物体都进化出独特的分子机制来产生这些节奏，但大多数生物钟都是由相互连接的转录和翻译反馈回路组成的。生物钟必须产生24小时的节律，使其节律与主要的明暗周期相适应，并适应各种其他环境扰动。数学建模已经成为一个强大的工具，用于解开驱动昼夜节律的分子反馈回路的复杂性（1）。然而，这种方法的真实的力量是揭示了昼夜节律系统建模与分子生物学实验紧密结合，专门设计用于生成数据的模型开发和验证（2）。粗糙脉孢菌是一个广泛研究的模型系统，用于理解昼夜节律的分子基础（3）。主要的负反馈环由两种蛋白质WC-1和WC-2启动，形成WCC复合物，其激活frq基因的转录（图1A）。该基因被翻译成FRQ蛋白，该蛋白与其他分子结合以形成从细胞质转运到细胞核的复合物。这种核复合物使WCC失活，因此抑制frq转录以实现负反馈。FRQ蛋白还增强WC-1积累，因此通过正反馈机制增加WCC。最近的一项研究（4）揭示了WCC控制下的一种新的转录调节因子CSP-1，它以葡萄糖依赖的方式抑制wc-1基因，形成另一个负反馈环。实验表明，这种反馈回路对于在葡萄糖浓度范围内保持昼夜节律周期近似恒定至关重要（4）。然而，相互关联的反馈回路的复杂性排除了通过纯实验手段对这种葡萄糖补偿机制的完全理解。Dovzhenok等人的一项新研究(5)发表在本期《生物物理杂志》上的文章通过湿实验室和计算实验的示例性组合研究了脉孢菌昼夜节律钟中的葡萄糖补偿。在许多方面，这项研究是Sancar等人发表的令人兴奋的实验工作的延续。(4)他们假设葡萄糖补偿是通过仔细平衡WC-1和CSP-1的表达来实现的。Dovzhenok及其同事的分子模型是通过将WCC/CSP-1/wc-1负反馈回路并入现有模型中来开发的，该模型考虑了其他两个回路（6）。为了验证模型预测，用野生型菌株和wc-1过表达突变体进行湿实验室实验，两者都含有wc-1荧光素酶报告基因以真实的时间监测推定的葡萄糖补偿环的行为。
The circadian clock generates 24-h rhythms that provide robust regulation of a variety of physiological and behavioral processes in a diverse range of organisms, including the fungus Neurospora, the plant Arabidopsis, the fly Drosophila, and mammals. While each organism has evolved unique molecular machinery to generate these rhythms, most circadian clocks are composed of interconnected transcriptional and translational feedback loops. The clock must generate robust 24-h rhythms, entrain its rhythms to the prevailing light-dark cycle, and adapt to various other environmental perturbations. Mathematical modeling has emerged as a powerful tool for unraveling the complexity of the molecular feedback loops that drive circadian rhythms (1). However, the real power of this approach is revealed when circadian systems modeling is tightly integrated with molecular biological experiments specifically designed to generate data for model development and validation (2). Neurospora crassa is a widely studied model system for understanding the molecular basis of circadian rhythmicity (3). The main negative feedback loop is initiated by two proteins, WC-1 and WC-2, forming the WCC complex, which activates the transcription of the frq gene (Fig. 1 A). This gene is translated into the FRQ protein, which binds to other molecules to form a complex that is transported from the cytoplasm into the nucleus. This nuclear complex inactivates WCC and therefore inhibits frq transcription to achieve negative feedback. The FRQ protein also enhances WC-1 accumulation and therefore increases WCC through a positive feedback mechanism. A recent study (4) has revealed a new transcriptional regulator CSP-1 under WCC control that represses the gene wc-1 in a glucosedependent fashion, forming another negative feedback loop. Experiments have suggested that this feedback loop is critical for maintaining the circadian period as approximately constant over a range of glucose concentrations (4). However, the complexity of the interconnected feedback loops precludes complete understanding of this glucose compensation mechanism through purely experimental means. A new study by Dovzhenok et al.(5) published in this issue of the Biophysical Journal examines glucose compensation in the Neurospora circadian clock through an exemplary combination of wet lab and computational experiments. In many ways, the study is a continuation of the exciting experimental work published by Sancar et al.(4), who hypothesized that glucose compensation is achieved by a careful balancing of wc-1 and csp-1 expression. The molecular model of Dovzhenok and coworkers was developed by incorporating the WCC/CSP-1/wc-1 negative feedback loop into an existing model that accounts for the other two loops (6). To validate the model predictions, wet lab experiments were performed with a wildtype strain and a wc-1 overexpression mutant, both containing a wc-1 luciferase reporter to monitor the behavior of the putative glucose compensation loop in real time.