Large-Scale Computational Modeling of Genetic Regulatory Networks

Recent advances of experimental techniques in biology have led to the production of enormous amounts of data on the dynamics of genetic regulatory networks. In this paper, we present an approach for the identification of PieceWise-Affine (PWA) models of genetic regulatory networks from experimental data, focusing on the reconstruction of switching thresholds associated with regulatory interactions. In particular, our method takes into account geometric constraints specific to models of genetic regulatory networks. We show the feasibility of our approach by the reconstruction of switching thresholds in a PWA model of the carbon starvation response in the bacterium Escherichia coli.

Systems of ordinary differential equations (ODE) of special form are considered in this paper. These systems appear in various models of genetic regulatory networks and telecommunication networks. The model of a genetic network with a chaotic attractor of dimension four is constructed. Geometrical considerations are used to study the properties of the systems. Computation of Lyapunov exponents is used to prove the existence of chaotic attractors. Problems of control and management of such regulatory systems are challenging issues in the theory of genetic networks.

In this paper, we investigate the oscillatory expression in Escherichia coli mediated by microRNA with time delays and reaction-diffusion terms. First of all, the integrated effects of delays and diffusions are first introduced into the genetic regulatory networks involving microRNAs, and a general model of genetic regulatory networks is then formulated. Second, two functional issues on gene regulatory networks, i.e. stability and oscillation of such model, are addressed in detail, and an explicit algorithm determining the properties of periodic oscillation is also presented. We demonstrate that the oscillatory expression of Escherichia coli is not only crucially dependent on the transcriptional and translational delays, but also heavily influenced by the diffusion coefficients. The conclusion is practically verified by a lot of biological experiments and observations. We also find that if the diffusion coefficients of miRNA, mRNA, and protein are suitably small, it can predict that inhomogeneous periodic oscillations can occur unless there only exhibits spatially homogeneous periodic oscillations. The obtained results indicate that the effects of transcriptional and translational delays are essential factors for designing or controlling genetic regulatory networks, in the meantime the functions of reaction-diffusion must beconsidered. Finally, numerical examples are presented to illustrate and visualize theoretical results.

In this paper, we propose a mean-field model which attempts to bridge the gap between random Boolean networks and more realistic stochastic modelling of genetic regulatory networks. The main idea of the model is to replace all regulatory interactions to any one gene with an average or effective interaction, which takes into account the repression and activation mechanisms. We find that depending on the set of regulatory parameters, the model exhibits rich nonlinear dynamics. The model also provides quantitative support to the earlier qualitative results obtained for random Boolean networks.

In order to understand the functioning of organisms on the molecular level, we need to know which genes are expressed, when and where in the organism, and to which extent. The regulation of gene expression is achieved through genetic regulatory systems structured by networks of interactions between DNA, RNA, proteins, and small molecules. As most genetic regulatory networks of interest involve many components connected through interlocking positive and negative feedback loops, an intuitive understanding of their dynamics is hard to obtain. As a consequence, formal methods and computer tools for the modeling and simulation of genetic regulatory networks will be indispensable. This paper reviews formalisms that have been employed in mathematical biology and bioinformatics to describe genetic regulatory systems, in particular directed graphs, Bayesian networks, Boolean networks and their generalizations, ordinary and partial differential equations, qualitative differential equations, stochastic equations, and rule-based formalisms. In addition, the paper discusses how these formalisms have been used in the simulation of the behavior of actual regulatory systems.

Analysis of the attractors of a genetic regulatory network gives a good indication of the possible functional modes of the system. In this paper we are concerned with the problem of finding all steady states of genetic regulatory networks described by piecewise-linear differential equation (PLDE) models. We show that the problem is NP-hard and translate it into a propositional satisfiability (SAT) problem. This allows the use of existing, efficient SAT solvers and has enabled the development of a steady state search module of the computer tool Genetic Network Analyzer (GNA). The practical use of this module is demonstrated by means of the analysis of a number of relatively small bacterial regulatory networks as well as randomly generated networks of several hundreds of genes.

In this paper, we propose a refinement of the modelling of biological regulatory networks based on the discrete approach of Rene Thomas. We refine and automatise the use of delays of activation/inhibition in order to specify which variable is more quickly affected by a change of its regulators. The formalism of linear hybrid automata is well suited to allow such refinement. We then use HyTech for two purposes: to find automatically all paths from a specified initial state to another one; to synthesise constraints on the delay parameters in order to follow any specific path.

BackgroundNumerous approaches exist for modeling of genetic regulatory networks (GRNs) but the low sampling rates often employed in biological studies prevents the inference of detailed models from experimental data. In this paper, we analyze the issues involved in estimating a model of a GRN from single cell line time series data with limited time points.ResultsWe present an inference approach for a Boolean Network (BN) model of a GRN from limited transcriptomic or proteomic time series data based on prior biological knowledge of connectivity, constraints on attractor structure and robust design. We applied our inference approach to 6 time point transcriptomic data on Human Mammary Epithelial Cell line (HMEC) after application of Epidermal Growth Factor (EGF) and generated a BN with a plausible biological structure satisfying the data. We further defined and applied a similarity measure to compare synthetic BNs and BNs generated through the proposed approach constructed from transitions of various paths of the synthetic BNs. We have also compared the performance of our algorithm with two existing BN inference algorithms.ConclusionsThrough theoretical analysis and simulations, we showed the rarity of arriving at a BN from limited time series data with plausible biological structure using random connectivity and absence of structure in data. The framework when applied to experimental data and data generated from synthetic BNs were able to estimate BNs with high similarity scores. Comparison with existing BN inference algorithms showed the better performance of our proposed algorithm for limited time series data. The proposed framework can also be applied to optimize the connectivity of a GRN from experimental data when the prior biological knowledge on regulators is limited or not unique.

A well‐known hypothesis, with far‐reaching implications, is that biological evolution should preferentially lead to states that are dynamically critical. In previous papers, we showed that a well‐known model of genetic regulatory networks, namely, that of random Boolean networks, allows one to study in depth the relationship between the dynamical regime of a living being’s gene network and its response to permanent perturbations. In this paper, we analyze a huge set of new experimental data on single gene knockouts in S. cerevisiae, laying down a statistical framework to determine its dynamical regime. We find that the S. cerevisiae network appears to be slightly ordered, but close to the critical region. Since our analysis relies on dichotomizing continuous data, we carefully consider the issue of an optimal threshold choice.

Symbolic reachability analysis of genetic regulatory networks using discrete abstractions

Random Boolean networks have been proposed as a basic model of genetic regulatory networks for more than four decades. Attractors have been considered as the best way to represent the long-term behaviors of random Boolean networks. Most studies on attractors are made with random topologies. However, the real regulatory networks have been found to be modular or more complex topologies. In this work, we extend classical robustness and entropy analysis of random Boolean networks to random modular Boolean networks. We firstly focus on the robustness of the attractor to perturbations with different parameters. Then, we investigate and calculate how the amount of information propagated between the nodes when on an attractor, as quantified by the average pairwise mutual information. The results can be used to study the capability of genetic information propagation of different types of genetic regulatory networks.

Type-dependent irreversible stochastic spin models for genetic regulatory networks at the level of promotion–inhibition circuitry

Identification of parameters and structure of piecewise affine models of genetic networks

The lack of precise numerical information for the values of biological parameters severely limits the development and analysis of models of genetic regulatory networks. To deal with this problem, we propose a method for the analysis of genetic regulatory networks with parameter uncertainty. We consider models based on piecewise-multiaffine differential equations, dynamical properties expressed in temporal logic, and intervals for the values of uncertain parameters. The problem is then either to guarantee that the system satisfies the expected properties for every possible parameter value - the corresponding parameter set is then called valid - or to find valid subsets of a given parameter set. The proposed method uses discrete abstractions and model checking, and allows for efficient search of the parameter space. This approach has been implemented in a tool for robust verification of gene networks (RoVerGeNe) and applied to the tuning of a synthetic network build in E. coli.

Bistability arises within a wide range of biological systems from the lambda phage switch in bacteria to cellular signal transduction pathways in mammalian cells. Changes in regulatory mechanisms may result in genetic switching in a bistable system. Recently, more and more experimental evidence in the form of bimodal population distributions indicates that noise plays a very important role in the switching of bistable systems. Although deterministic models have been used for studying the existence of bistability properties under various system conditions, these models cannot realize cell-to-cell fluctuations in genetic switching. However, there is a lag in the development of stochastic models for studying the impact of noise in bistable systems because of the lack of detailed knowledge of biochemical reactions, kinetic rates, and molecular numbers. In this work, we develop a previously undescribed general technique for developing quantitative stochastic models for large-scale genetic regulatory networks by introducing Poisson random variables into deterministic models described by ordinary differential equations. Two stochastic models have been proposed for the genetic toggle switch interfaced with either the SOS signaling pathway or a quorum-sensing signaling pathway, and we have successfully realized experimental results showing bimodal population distributions. Because the introduced stochastic models are based on widely used ordinary differential equation models, the success of this work suggests that this approach is a very promising one for studying noise in large-scale genetic regulatory networks.