Equation-free analysis of two-component system signalling model reveals the emergence of co-existing phenotypes in the absence of multistationarity.
Equation-free analysis of two-component system signalling model reveals the emergence of co-existing phenotypes in the absence of multistationarity.
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DOI：
10.1371/journal.pcbi.1002396
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发表时间：
2012
影响因子：
4.3
通讯作者：
Kierzek AM
中科院分区：
文献类型：
--
作者：
Hoyle RB;Avitabile D;Kierzek AM
遗传上相同的细胞在相同的环境条件下的表型差异归因于生化过程的内在随机性。已经提出了各种机制，包括通过随机波动、从稳定状态到不稳定激发状态的长时间瞬态偏移以及根据组成化学物质的可用性打开和关闭反应网络来达到的调节网络中的替代稳定状态的存在。在这里，我们分析了一个详细的随机动力学模型的双组分系统的信号在细菌中，并表明，替代表型出现在没有这些功能。我们进行了分岔分析的确定性反应速率方程从模型中得出，并发现，他们不能再现整个范围内的定性反应的外部信号所表现出的直接随机模拟。特别是，混合模式，其中随机开关和分级响应被同时看到，是不存在的。然而，概率和方程的随机模型，计算稳态的一个合奏的随机轨迹的平均值的分析表明，慢转录的反应调节或组氨酸激酶导致共存的近似基础的解决方案和一个分级的响应，联合收割机结合产生的混合模式，从而建立其基本的随机性质。同样的技术还表明，随机性导致在比确定性基础上所预期的更宽的外部信号范围内观察到全或无响应。因此，我们证明了应用数值方程的方法，一个详细的生化反应网络模型，并表明它可以提供新的洞察随机性的作用，在出现的表型多样性。一个令人惊讶的事实是，基因相同的细菌，生活在相同的条件下，可以以完全不同的方式发展：例如，一个亚群可能生长得非常快，另一个非常慢。这些不同的表型被认为是导致疾病的细菌可以在抗生素治疗中存活或变得持久的原因之一。这种行为的多样性通常归因于多种稳定的表型状态的存在，或者归因于一种稳定状态与另一种不稳定的激发状态的共存，或者最终归因于控制表型的整个生化系统被打开和关闭的可能性。在本文中，我们描述了一种不同的情况下，导致表型多样性的双组分系统信号，一个非常常见的机制，细菌用来感知外部信号，并控制他们的反应，在他们的环境变化。我们使用概率论和方程的计算分析，计算的平均分子数的每个化学物种中存在的两种成分的系统，因此表明，零星生产的两个关键的化学成分所需的信号可以延迟响应的外部信号在一些细菌细胞，从而导致出现两个不同的细胞群体。
Phenotypic differences of genetically identical cells under the same environmental conditions have been attributed to the inherent stochasticity of biochemical processes. Various mechanisms have been suggested, including the existence of alternative steady states in regulatory networks that are reached by means of stochastic fluctuations, long transient excursions from a stable state to an unstable excited state, and the switching on and off of a reaction network according to the availability of a constituent chemical species. Here we analyse a detailed stochastic kinetic model of two-component system signalling in bacteria, and show that alternative phenotypes emerge in the absence of these features. We perform a bifurcation analysis of deterministic reaction rate equations derived from the model, and find that they cannot reproduce the whole range of qualitative responses to external signals demonstrated by direct stochastic simulations. In particular, the mixed mode, where stochastic switching and a graded response are seen simultaneously, is absent. However, probabilistic and equation-free analyses of the stochastic model that calculate stationary states for the mean of an ensemble of stochastic trajectories reveal that slow transcription of either response regulator or histidine kinase leads to the coexistence of an approximate basal solution and a graded response that combine to produce the mixed mode, thus establishing its essential stochastic nature. The same techniques also show that stochasticity results in the observation of an all-or-none bistable response over a much wider range of external signals than would be expected on deterministic grounds. Thus we demonstrate the application of numerical equation-free methods to a detailed biochemical reaction network model, and show that it can provide new insight into the role of stochasticity in the emergence of phenotypic diversity. It is a surprising fact that genetically identical bacteria, living in identical conditions, can develop in completely different ways: for example, one subpopulation might grow very fast and another very slowly. These different phenotypes are thought to be one reason why bacteria that cause disease can survive antibiotic treatment or become persistent. This diversity of behaviour is usually attributed to the existence of multiple stable phenotypic states, or to the coexistence of one stable state with another unstable excited state, or finally to the possibility of the whole biochemical system that controls the phenotype being switched on and off. In this paper we describe a different scenario that leads to phenotypic diversity in two-component system signalling, a very common mechanism that bacteria use to sense external signals and control their response to changes in their environment. We use probability theory and equation-free computational analysis to calculate the average number of molecules of each chemical species present in the two-component system and hence show that sporadic production of either of two key chemical components required for signalling can delay the response to the external signal in some bacterial cells and so lead to the emergence of two distinct cell populations.
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影响因子：
56.9
作者：
Maamar, Hedia;Raj, Arjun;Dubnau, David
通讯作者：
Dubnau, David
影响因子：
2
作者：
Karmakar, Rajesh;Bose, Indrani
通讯作者：
Bose, Indrani
影响因子：
4.4
作者：
Erban, Radek;Frewen, Thomas A.;Kevrekidis, Ioannis G.
通讯作者：
Kevrekidis, Ioannis G.
影响因子：
4.8
作者：
Cai, SJ;Inouye, M
通讯作者：
Inouye, M
DOI：
10.1073/pnas.1631248100
发表时间：
2003-08-19
影响因子：
11.1
作者：
Dahl, JL;Kraus, CN;Barry, CE
通讯作者：
Barry, CE