Sturrock M, Murray P J, Matzavinos A, Chaplain M A J
Mathematical Biosciences Institute, The Ohio State University, Columbus, OH, 43210, USA,
J Math Biol. 2015 Oct;71(4):921-59. doi: 10.1007/s00285-014-0837-0. Epub 2014 Oct 17.
A gene regulatory network may be defined as a collection of DNA segments which interact with each other indirectly through their RNA and protein products. Such a network is said to contain a negative feedback loop if its products inhibit gene transcription, and a positive feedback loop if a gene product promotes its own production. Negative feedback loops can create oscillations in mRNA and protein levels while positive feedback loops are primarily responsible for signal amplification. It is often the case in real biological systems that both negative and positive feedback loops operate in parameter regimes that result in low copy numbers of gene products. In this paper we investigate the spatio-temporal dynamics of a single feedback loop in a eukaryotic cell. We first develop a simplified spatial stochastic model of a canonical feedback system (either positive or negative). Using a Gillespie's algorithm, we compute sample trajectories and analyse their corresponding statistics. We then derive a system of equations that describe the spatio-temporal evolution of the stochastic means. Subsequently, we examine the spatially homogeneous case and compare the results of numerical simulations with the spatially explicit case. Finally, using a combination of steady-state analysis and data clustering techniques, we explore model behaviour across a subregion of the parameter space that is difficult to access experimentally and compare the parameter landscape of our spatio-temporal and spatially-homogeneous models.
基因调控网络可定义为一组DNA片段,它们通过RNA和蛋白质产物相互间接作用。如果该网络的产物抑制基因转录,则称其包含负反馈环;如果基因产物促进自身产生,则称其包含正反馈环。负反馈环可在mRNA和蛋白质水平上产生振荡,而正反馈环主要负责信号放大。在实际生物系统中,负反馈环和正反馈环通常在导致基因产物拷贝数较低的参数范围内运行。在本文中,我们研究了真核细胞中单个反馈环的时空动态。我们首先开发了一个典型反馈系统(正反馈或负反馈)的简化空间随机模型。使用 Gillespie算法,我们计算样本轨迹并分析其相应的统计数据。然后,我们推导了一个描述随机均值时空演化的方程组。随后,我们研究空间均匀情况,并将数值模拟结果与空间显式情况进行比较。最后,结合稳态分析和数据聚类技术,我们探索了参数空间中一个难以通过实验访问的子区域内的模型行为,并比较了我们的时空模型和空间均匀模型的参数格局。