Models Of Genetic Regulatory Networks Research Articles

A Model for Genetic and Epigenetic Regulatory Networks Identifies Rare Pathways for Transcription Factor Induced Pluripotency

With relatively low efficiency, differentiated cells can be reprogrammed to a pluripotent state by ectopic expression of a few transcription factors. An understanding of the mechanisms that underlie data emerging from such experiments can help design optimal strategies for creating pluripotent cells for patient-specific regenerative medicine. We have developed a computational model for the architecture of the epigenetic and genetic regulatory networks which describes transformations resulting from expression of reprogramming factors. Importantly, our studies identify the rare temporal pathways that result in induced pluripotent cells. Further experimental tests of predictions emerging from our model should lead to fundamental advances in our understanding of how cellular identity is maintained and transformed.

Stationary and oscillatory fronts in a two-component genetic regulatory network model

We investigate a two-component gene network model, originally used to describe the spatiotemporal patterning of the gene products in early Drosophila development. By considering a particular mode of interaction between the two gene products, denoted proteins A and B , we find both stable stationary and time-oscillatory fronts can occur in the reaction–diffusion system. We reduce the system by replacing B with its spatial average (shadow system) and assume an abrupt “on-and-off” switch for the genes. In doing so, explicit formula are obtained for all steady-state solutions and their linear eigenvalues. Using the diffusion of A , D a , and the basal production rate, r , as bifurcation parameters, we explore ranges in which a monotone, stationary front is stable, and show it can lose stability through a Hopf bifurcation, giving rise to oscillatory fronts. We also discuss the existence and stability of steady-state and time-oscillatory solutions with multiple extrema. An intuitive explanation for the occurrence of stable stationary and oscillatory front solutions is provided based on the behavior of A in the absence of B and the opposite regulation between A and B . Such behavior is also interpreted in terms of the biological parameters in the model, including those governing the connection of the gene network.

On the dynamics of random Boolean networks subject to noise: Attractors, ergodic sets and cell types

The asymptotic dynamics of random Boolean networks subject to random fluctuations is investigated. Under the influence of noise, the system can escape from the attractors of the deterministic model, and a thorough study of these transitions is presented. We show that the dynamics is more properly described by sets of attractors rather than single ones. We generalize here a previous notion of ergodic sets, and we show that the Threshold Ergodic Sets so defined are robust with respect to noise and, at the same time, that they do not suffer from a major drawback of ergodic sets. The system jumps from one attractor to another of the same Threshold Ergodic Set under the influence of noise, never leaving it. By interpreting random Boolean networks as models of genetic regulatory networks, we also propose to associate cell types to Threshold Ergodic Sets rather than to deterministic attractors or to ergodic sets, as it had been previously suggested. We also propose to associate cell differentiation to the process whereby a Threshold Ergodic Set composed by several attractors gives rise to another one composed by a smaller number of attractors. We show that this approach accounts for several interesting experimental facts about cell differentiation, including the possibility to obtain an induced pluripotent stem cell from a fully differentiated one by overexpressing some of its genes.

Identification of genetic network dynamics with unate structure

Modern experimental techniques for time course measurement of gene expression enable the identification of dynamical models of genetic regulatory networks. In general, identification involves fitting appropriate network structures and parameters to the data. For a given set of genes, exploring all possible network structures is clearly prohibitive. Modelling and identification methods for the a priori selection of network structures compatible with biological knowledge and experimental data are necessary to make the identification problem tractable. We propose a differential equation modelling framework where the regulatory interactions among genes are expressed in terms of unate functions, a class of gene activation rules commonly encountered in Boolean network modelling. We establish analytical properties of the models in the class and exploit them to devise a two-step procedure for gene network reconstruction from product concentration and synthesis rate time series. The first step isolates a family of model structures compatible with the data from a set of most relevant biological hypotheses. The second step explores this family and returns a pool of best fitting models along with estimates of their parameters. The method is tested on a simulated network and compared with state-of-the-art network inference methods on the benchmark synthetic network IRMA.

A Model For Genetic and Epigenetic Regulatory Networks Identifies Rare Pathways For Transcription Factor Induced Pluripotency

With relatively low efficiency, differentiated cells can be reprogrammed to a pluripotent state by ectopic expression of a few transcription factors. An understanding of the mechanisms that underlie data emerging from such experiments can help design optimal strategies for creating pluripotent cells for patient-specific regenerative medicine. We have developed a computational model for the architecture of the epigenetic and genetic regulatory networks which describes transformations resulting from expression of reprogramming factors. Importantly, our studies identify the rare temporal pathways that result in induced pluripotent cells. Further experimental tests of predictions emerging from our model should lead to fundamental advances in our understanding of how cellular identity is maintained and transformed.

Are genetically robust regulatory networks dynamically different from random ones?

We study a genetic regulatory network model developed to demonstrate that genetic robustness can evolve through stabilizing selection for optimal phenotypes. We report preliminary results on whether such selection could result in a reorganization of the state space of the system. For the chosen parameters, the evolution moves the system slightly toward the more ordered part of the phase diagram. We also find that strong memory effects cause the Derrida annealed approximation to give erroneous predictions about the model’s phase diagram.

A service-oriented architecture for integrating the modeling and formal verification of genetic regulatory networks

BackgroundThe study of biological networks has led to the development of increasingly large and detailed models. Computer tools are essential for the simulation of the dynamical behavior of the networks from the model. However, as the size of the models grows, it becomes infeasible to manually verify the predictions against experimental data or identify interesting features in a large number of simulation traces. Formal verification based on temporal logic and model checking provides promising methods to automate and scale the analysis of the models. However, a framework that tightly integrates modeling and simulation tools with model checkers is currently missing, on both the conceptual and the implementational level.ResultsWe have developed a generic and modular web service, based on a service-oriented architecture, for integrating the modeling and formal verification of genetic regulatory networks. The architecture has been implemented in the context of the qualitative modeling and simulation tool GNA and the model checkers NUSMV and CADP. GNA has been extended with a verification module for the specification and checking of biological properties. The verification module also allows the display and visual inspection of the verification results.ConclusionsThe practical use of the proposed web service is illustrated by means of a scenario involving the analysis of a qualitative model of the carbon starvation response in E. coli. The service-oriented architecture allows modelers to define the model and proceed with the specification and formal verification of the biological properties by means of a unified graphical user interface. This guarantees a transparent access to formal verification technology for modelers of genetic regulatory networks.

Fuzzy Logic in Genetic Regulatory Network Models

<p>Interactions between genes and the proteins they synthesize shape genetic regulatory networks (GRN). Several models have been proposed to describe these interactions, been the most commonly used those based on ordinary differential equations (ODEs). Some approximations using piecewise linear differential equations (PLDEs), have been proposed to simplify the model non linearities. However they not allways give good results. In this context, it has been developed a model capable of representing small GRN, combining characteristics from the ODE’s models and fuzzy inference systems (FIS). The FIS is trained through an artificial neural network, which forms an Adaptive Nertwork-based Fuzzy Inference System (ANFIS). This network allows to adapt the membership and output functions from the FIS according to the training data, thus, reducing the previous knowledge needed to model the specific phenomenon.<br /> In addition, Fuzzy Logic allows to express their rules through linguistic labels, which also allows to incorporate expert knowledge in a friendly way. The proposed model has been used to describe the Lac Operon in E. Coli and it has been compared with the models already mentioned. The outcome errors due to the training process of the ANFIS network are comparable with those of the models based on ODEs. Additionally, the fuzzy logic approach provides modeling flexibility and knowledge acquisition advantages.</p>

On the Transient and Steady-State Estimates of Interval Genetic Regulatory Networks

This paper is concerned with the transient and steady-state estimates of a class of genetic regulatory networks (GRNs). Some sufficient conditions, which do not only present the transient estimate but also provide the estimates of decay rate and decay coefficient of the GRN with interval parameter uncertainties (interval GRN), are established by means of linear matrix inequality (LMI) and Lyapunov-Krasovskii functional. Moreover, the steady-state estimate of the proposed GRN model is also investigated. Furthermore, it is well known that gene regulation is an intrinsically noisy process due to intracellular and extracellular noise perturbations and environmental fluctuations. Then, by utilizing stochastic differential equation theory, the obtained results are extended to the case with noise perturbations due to natural random fluctuations. All the conditions are expressed within the framework of LMIs, which can easily be computed by using standard numerical software. A three-gene network is provided to illustrate the effectiveness of the theoretical results.

A multi-objective differential evolutionary approach toward more stable gene regulatory networks

Models are of central importance in many scientific contexts. Mathematical and computational modeling of genetic regulatory networks promises to uncover the fundamental principles of living systems. Biological models, such as gene regulatory models, can help us better understand interactions among genes and how cells regulate their production of proteins and enzymes. One feature shared among living systems is their ability to cope with perturbations and remain stable, a property that is the result of evolutionary fine-tuning over many generations. In this study we use random Boolean networks (RBNs) as an abstract model of gene regulatory systems. By applying Differential Evolution (DE), an evolution-based optimization technique, we produce networks with increased stability. DE requires relatively few user-specified parameters, has fast convergence and does not rely on initial conditions to find the global minima within multi-dimensional search spaces. The stability of networks is evaluated by taking parameters such as their network sensitivity, attractor cycle length and number of attractor basins into account. In this study we present an evolutionary approach to produce networks with specific properties (high stability) starting from chaotic regimes. From this chaotic regime and randomly generated classical RBNs with static input degree, our evolutionary approach is able to produce networks with homogenous Boolean functions and highly structured state spaces.

Comparing different ODE modelling approaches for gene regulatory networks

A fundamental step in synthetic biology and systems biology is to derive appropriate mathematical models for the purposes of analysis and design. For example, to synthesize a gene regulatory network, the derivation of a mathematical model is important in order to carry out in silico investigations of the network dynamics and to investigate parameter variations and robustness issues. Different mathematical frameworks have been proposed to derive such models. In particular, the use of sets of nonlinear ordinary differential equations (ODEs) has been proposed to model the dynamics of the concentrations of mRNAs and proteins. These models are usually characterized by the presence of highly nonlinear Hill function terms. A typical simplification is to reduce the number of equations by means of a quasi-steady-state assumption on the mRNA concentrations. This yields a class of simplified ODE models. A radically different approach is to replace the Hill functions by piecewise-linear approximations [Casey, R., de Jong, H., Gouz e ´ , J.-L., 2006. Piecewise-linear models of genetic regulatory networks: equilibria and their stability. J. Math. Biol. 52 (1), 27–56]. A further modelling approach is the use of discrete-time maps [Coutinho, R., Fernandez, B., Lima, R., Meyroneinc, A., 2006. Discrete time piecewise affine models of genetic regulatory networks. J. Math. Biol. 52, 524–570] where the evolution of the system is modelled in discrete, rather than continuous, time. The aim of this paper is to discuss and compare these different modelling approaches, using a representative gene regulatory network. We will show that different models often lead to conflicting conclusions concerning the existence and stability of equilibria and stable oscillatory behaviours. Moreover, we shall discuss, where possible, the viability of making certain modelling approximations (e.g. quasi-steady-state mRNA dynamics or piecewise-linear approximations of Hill functions) and their effects on the overall system dynamics.

A declarative constraint-based method for analyzing discrete genetic regulatory networks

Dynamical modeling has proven useful for understanding how complex biological processes emerge from the many components and interactions composing genetic regulatory networks (GRNs). However, the development of models is hampered by large uncertainties in both the network structure and parameter values. To remedy this problem, the models are usually developed through an iterative process based on numerous simulations, confronting model predictions with experimental data and refining the model structure and/or parameter values to repair the inconsistencies. In this paper, we propose an alternative to this generate-and-test approach. We present a four-step method for the systematic construction and analysis of discrete models of GRNs by means of a declarative approach. Instead of instantiating the models as in classical modeling approaches, the biological knowledge on the network structure and its dynamics is formulated in the form of constraints. The compatibility of the network structure with the constraints is queried and in case of inconsistencies, some constraints are relaxed. Common properties of the consistent models are then analyzed by means of dedicated languages. Two such languages are introduced in the paper. Removing questionable constraints or adding interesting ones allows to further analyze the models. This approach allows to identify the best experiments to be carried out, in order to discriminate sets of consistent models and refine our knowledge on the system functioning. We test the feasibility of our approach, by applying it to the re-examination of a model describing the nutritional stress response in the bacterium Escherichia coli.

Stochastic stability of Markovian switching genetic regulatory networks

In this Letter, taking into account the structure variations at discrete time instances during the process of gene regulation, a hybrid genetic regulatory networks model based on Markov chain is proposed. Its robust stochastic stability in the case of uncertain switching probabilities and intrinsic noises is then addressed from the stochastic system point of view. It is shown that the sufficient condition for the robust stochastic stability of the genetic networks can be formulated as feasibility of a linear matrix inequality, which can be easily facilitated by Matlab LMI toolbox. Finally, a numerical example with simulations is presented to illustrate the effectiveness of the developed results.

On algorithmic analysis of transcriptional regulation by LTL model checking

Studies of cells in silico can greatly reduce the need for expensive and prolonged laboratory experimentation. The use of model checking for the analysis of biological networks has attracted much attention recently. The practical limitations are still the size of the model, and the time needed to generate the state space. This paper is focused on the model checking approach for analysis of piecewise-linear deterministic models of genetic regulatory networks. Firstly, the qualitative simulation algorithm of de Jong et al. that builds the heart of Genetic Network Analyzer (GNA) is revisited and its time complexity is studied in detail. Secondly, a novel algorithm that reduces the state space generation time is introduced. The new algorithm is developed as an abstraction of the original GNA algorithm. Finally, a fragment of linear time temporal logic for which the provided abstraction is conservative is identified. Efficiency of the new algorithm when implemented in the parallel model checking environment is demonstrated on a set of experiments performed on randomly modified biological models. In general, the achieved results bring a new insight into the field of qualitative simulation emerging in the context of systems biology.

The Switching Threshold Reconstruction Problem for Piecewise Affine Models 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. 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.

Temporal Logic Analysis of Gene Netwroks Under parameter uncertainty

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 under 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. However, the abstraction process creates spurious behaviors in the abstract systems, along which time does not progress. Consequently, the verification of liveness properties, expressing that something will eventually happen, and implicitly assuming progress of time, often fails. A solution to this second problem is proposed using the notion of transient regions. This approach has been implemented in a tool for robust verification of gene networks and applied to the tuning of a synthetic network built in <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">E. coli</i> .

Chapter 13 - Deterministic and Stochastic Models of Genetic Regulatory Networks

Traditionally molecular biology research has tended to reduce biological pathways to composite units studied as isolated parts of the cellular system. With the advent of high throughput methodologies that can capture thousands of data points, and powerful computational approaches, the reality of studying cellular processes at a systems level is upon us. As these approaches yield massive datasets, systems level analyses have drawn upon other fields such as engineering and mathematics, adapting computational and statistical approaches to decipher relationships between molecules. Guided by high quality datasets and analyses, one can begin the process of predictive modeling. The findings from such approaches are often surprising and beyond normal intuition. We discuss four classes of dynamical systems used to model genetic regulatory networks. The discussion is divided into continuous and discrete models, as well as deterministic and stochastic model classes. For each combination of these categories, a model is presented and discussed in the context of the yeast cell cycle, illustrating how different types of questions can be addressed by different model classes.

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

In this paper we consider piecewise affine models of genetic regulatory networks proposed by Glass and Kaufmann in the 70's and discuss a method for their identification. These systems have specific features that must be preserved by the identification procedure in order to obtain biologically meaningful models. Moreover, rather than producing a single hypothesis about the way genes interact, identification should produce alternatives consistent with the available data so as to provide biologists with multiple hypothesis about the network functioning. The input of the identification method consists of time-series measurements of concentrations of gene products. As outputs, estimates of the modes of operation of the GRN as well as all possible minimal combinations of threshold concentrations of the gene products accounting for switches between the modes of operation are provided. Individual steps of the identification method have been been described separately in previous publications and the main aim of this paper is to test the applicability of the whole procedure. To this purpose, we use simulated data obtained from a model of the carbon starvation response in the bacterium E. coli. In particular, performance of the method under different data characteristics, notably variations in the noise level and the sampling density, are discussed.

Structural Identification of Piecewise-Linear Models of Genetic Regulatory Networks

We present a method for the structural identification of genetic regulatory networks (GRNs), based on the use of a class of Piecewise-Linear (PL) models. These models consist of a set of decoupled linear models describing the different modes of operation of the GRN and discrete switches between the modes accounting for the nonlinear character of gene regulation. They thus form a compromise between the mathematical simplicity of linear models and the biological expressiveness of nonlinear models. The input of the PL identification method consists of time-series measurements of concentrations of gene products. As output it produces estimates of the modes of operation of the GRN, as well as all possible minimal combinations of threshold concentrations of the gene products accounting for switches between the modes of operation. The applicability of the PL identification method has been evaluated using simulated data obtained from a model of the carbon starvation response in the bacterium Escherichia coli. This has allowed us to systematically test the performance of the method under different data characteristics, notably variations in the noise level and the sampling density.

A Publish-Subscribe Model of Genetic Networks

We present a simple model of genetic regulatory networks in which regulatory connections among genes are mediated by a limited number of signaling molecules. Each gene in our model produces (publishes) a single gene product, which regulates the expression of other genes by binding to regulatory regions that correspond (subscribe) to that product. We explore the consequences of this publish-subscribe model of regulation for the properties of single networks and for the evolution of populations of networks. Degree distributions of randomly constructed networks, particularly multimodal in-degree distributions, which depend on the length of the regulatory sequences and the number of possible gene products, differed from simpler Boolean NK models. In simulated evolution of populations of networks, single mutations in regulatory or coding regions resulted in multiple changes in regulatory connections among genes, or alternatively in neutral change that had no effect on phenotype. This resulted in remarkable evolvability in both number and length of attractors, leading to evolved networks far beyond the expectation of these measures based on random distributions. Surprisingly, this rapid evolution was not accompanied by changes in degree distribution; degree distribution in the evolved networks was not substantially different from that of randomly generated networks. The publish-subscribe model also allows exogenous gene products to create an environment, which may be noisy or stable, in which dynamic behavior occurs. In simulations, networks were able to evolve moderate levels of both mutational and environmental robustness.