Pájaro Manuel, Alonso Antonio A, Otero-Muras Irene, Vázquez Carlos
Process Engineering Group, IIM-CSIC, Spanish Council for Scientific Research, Eduardo Cabello 6, 36208 - Vigo, Spain.
Department of Mathematics, University of A Coruña. Campus Elviña s/n, 15071 - A Coruña, Spain.
J Theor Biol. 2017 May 21;421:51-70. doi: 10.1016/j.jtbi.2017.03.017. Epub 2017 Mar 21.
Gene expression is inherently stochastic. Advanced single-cell microscopy techniques together with mathematical models for single gene expression led to important insights in elucidating the sources of intrinsic noise in prokaryotic and eukaryotic cells. In addition to the finite size effects due to low copy numbers, translational bursting is a dominant source of stochasticity in cell scenarios involving few short lived mRNA transcripts with high translational efficiency (as is typically the case for prokaryotes), causing protein synthesis to occur in random bursts. In the context of gene regulation cascades, the Chemical Master Equation (CME) governing gene expression has in general no closed form solution, and the accurate stochastic simulation of the dynamics of complex gene regulatory networks is a major computational challenge. The CME associated to a single gene self regulatory motif has been previously approximated by a one dimensional time dependent partial integral differential equation (PIDE). However, to the best of our knowledge, multidimensional versions for such PIDE have not been developed yet. Here we propose a multidimensional PIDE model for regulatory networks involving multiple genes with self and cross regulations (in which genes can be regulated by different transcription factors) derived as the continuous counterpart of a CME with jump process. The model offers a reliable description of systems with translational bursting. In order to provide an efficient numerical solution, we develop a semilagrangian method to discretize the differential part of the PIDE, combined with a composed trapezoidal quadrature formula to approximate the integral term. We apply the model and numerical method to study sustained stochastic oscillations and the development of competence, a particular case of transient differentiation attained by certain bacterial cells under stress conditions. We found that the resulting probability distributions are distinguishable from those characteristic of other transient differentiation processes. In this way, they can be employed as markers or signatures that identify such phenomena from bacterial population experimental data, for instance. The computational efficiency of the semilagrangian method makes it suitable for purposes like model identification and parameter estimation from experimental data or, in combination with optimization routines, the design of gene regulatory networks under molecular noise.
基因表达本质上是随机的。先进的单细胞显微镜技术以及单基因表达的数学模型,在阐明原核细胞和真核细胞内在噪声来源方面带来了重要见解。除了由于低拷贝数导致的有限尺寸效应外,翻译爆发是细胞场景中随机性的一个主要来源,这种场景涉及少量具有高翻译效率的短寿命mRNA转录本(原核生物通常如此),导致蛋白质合成以随机爆发的形式发生。在基因调控级联的背景下,控制基因表达的化学主方程(CME)通常没有封闭形式的解,对复杂基因调控网络动态进行准确的随机模拟是一项重大的计算挑战。与单个基因自调控基序相关的CME先前已由一维时间相关的偏积分微分方程(PIDE)近似。然而,据我们所知,尚未开发出此类PIDE的多维版本。在此,我们提出了一种用于涉及多个具有自我和交叉调控基因(其中基因可由不同转录因子调控)的调控网络的多维PIDE模型,该模型是作为具有跳跃过程的CME的连续对应物推导出来的。该模型为具有翻译爆发的系统提供了可靠的描述。为了提供一种有效的数值解,我们开发了一种半拉格朗日方法来离散PIDE的微分部分,并结合复合梯形求积公式来近似积分项。我们应用该模型和数值方法来研究持续的随机振荡以及感受态的发展,感受态是某些细菌细胞在应激条件下实现的一种特殊的瞬时分化情况。我们发现,所得的概率分布与其他瞬时分化过程的特征分布不同。通过这种方式,例如,它们可以用作标记或特征,从细菌群体实验数据中识别此类现象。半拉格朗日方法的计算效率使其适用于诸如从实验数据进行模型识别和参数估计等目的,或者与优化例程相结合,用于在分子噪声下设计基因调控网络。