Dynamics Of Genetic Regulatory Networks Research Articles

Inference of gene networks from gene expression time series using recurrent neural networks and sparse MAP estimation.

The inference of genetic regulatory networks (GRNs) provides insight into the cellular responses to signals. A class of recurrent neural networks (RNNs) capturing the dynamics of GRN has been used as a basis for inferring small-scale GRNs from gene expression time series. The Bayesian framework facilitates incorporating the hypothesis of GRN into the model estimation to improve the accuracy of GRN inference. We present new methods for inferring small-scale GRNs based on RNNs. The weights of wires of RNN represent the strengths of gene-to-gene regulatory interactions. We use a class of automatic relevance determination (ARD) priors to enforce the sparsity in the maximum a posteriori (MAP) estimates of wire weights of RNN. A particle swarm optimization (PSO) is integrated as an optimization engine into the MAP estimation process. Likely networks of genes generated based on estimated wire weights are combined using the majority rule to determine a final estimated GRN. As an alternative, a class of [Formula: see text] priors is used for attaining the sparse MAP estimates of wire weights of RNN. We also infer the GRN using the maximum likelihood (ML) estimates of wire weights of RNN. The RNN-based GRN inference algorithms, ARD-RNN, [Formula: see text] -RNN, and ML-RNN are tested on simulated and experimental E. coli and yeast time series containing 6-11 genes and 7-19 data points. Published GRN inference algorithms based on regressions and mutual information networks are performed on the benchmark datasets to compare performances. ARD and [Formula: see text] -norm priors are used for the estimation of wire weights of RNN. Results of GRN inference experiments show that ARD-RNN, [Formula: see text] -RNN have similar best accuracies on the simulated time series. The ARD-RNN is more accurate than [Formula: see text] -RNN, ML-RNN, and mostly more accurate than the reference algorithms on the experimental time series. The effectiveness of ARD-RNN for inferring small-scale GRNs using gene expression time series of limited length is empirically verified.

Reconstructing Genetic Regulatory Networks Using Two-Step Algorithms with the Differential Equation Models of Neural Networks

The identification of genetic regulatory networks (GRNs) provides insights into complex cellular processes. A class of recurrent neural networks (RNNs) captures the dynamics of GRN. Algorithms combining the RNN and machine learning schemes were proposed to reconstruct small-scale GRNs using gene expression time series. We present new GRN reconstruction methods with neural networks. The RNN is extended to a class of recurrent multilayer perceptrons (RMLPs) with latent nodes. Our methods contain two steps: the edge rank assignment step and the network construction step. The former assigns ranks to all possible edges by a recursive procedure based on the estimated weights of wires of RNN/RMLP (RERNN/RERMLP), and the latter constructs a network consisting of top-ranked edges under which the optimized RNN simulates the gene expression time series. The particle swarm optimization (PSO) is applied to optimize the parameters of RNNs and RMLPs in a two-step algorithm. The proposed RERNN-RNN and RERMLP-RNN algorithms are tested on synthetic and experimental gene expression time series of small GRNs of about 10 genes. The experimental time series are from the studies of yeast cell cycle regulated genes and E. coli DNA repair genes. The unstable estimation of RNN using experimental time series having limited data points can lead to fairly arbitrary predicted GRNs. Our methods incorporate RNN and RMLP into a two-step structure learning procedure. Results show that the RERMLP using the RMLP with a suitable number of latent nodes to reduce the parameter dimension often result in more accurate edge ranks than the RERNN using the regularized RNN on short simulated time series. Combining by a weighted majority voting rule the networks derived by the RERMLP-RNN using different numbers of latent nodes in step one to infer the GRN, the method performs consistently and outperforms published algorithms for GRN reconstruction on most benchmark time series. The framework of two-step algorithms can potentially incorporate with different nonlinear differential equation models to reconstruct the GRN.

An integrated approach to infer dynamic protein-gene interactions – A case study of the human P53 protein

Investigating the dynamics of genetic regulatory networks through high throughput experimental data, such as microarray gene expression profiles, is a very important but challenging task. One of the major hindrances in building detailed mathematical models for genetic regulation is the large number of unknown model parameters. To tackle this challenge, a new integrated method is proposed by combining a top-down approach and a bottom-up approach. First, the top-down approach uses probabilistic graphical models to predict the network structure of DNA repair pathway that is regulated by the p53 protein. Two networks are predicted, namely a network of eight genes with eight inferred interactions and an extended network of 21 genes with 17 interactions. Then, the bottom-up approach using differential equation models is developed to study the detailed genetic regulations based on either a fully connected regulatory network or a gene network obtained by the top-down approach. Model simulation error, parameter identifiability and robustness property are used as criteria to select the optimal network. Simulation results together with permutation tests of input gene network structures indicate that the prediction accuracy and robustness property of the two predicted networks using the top-down approach are better than those of the corresponding fully connected networks. In particular, the proposed approach reduces computational cost significantly for inferring model parameters. Overall, the new integrated method is a promising approach for investigating the dynamics of genetic regulation.

Modeling delay in genetic networks: from delay birth-death processes to delay stochastic differential equations.

Delay is an important and ubiquitous aspect of many biochemical processes. For example, delay plays a central role in the dynamics of genetic regulatory networks as it stems from the sequential assembly of first mRNA and then protein. Genetic regulatory networks are therefore frequently modeled as stochastic birth-death processes with delay. Here, we examine the relationship between delay birth-death processes and their appropriate approximating delay chemical Langevin equations. We prove a quantitative bound on the error between the pathwise realizations of these two processes. Our results hold for both fixed delay and distributed delay. Simulations demonstrate that the delay chemical Langevin approximation is accurate even at moderate system sizes. It captures dynamical features such as the oscillatory behavior in negative feedback circuits, cross-correlations between nodes in a network, and spatial and temporal information in two commonly studied motifs of metastability in biochemical systems. Overall, these results provide a foundation for using delay stochastic differential equations to approximate the dynamics of birth-death processes with delay.

Application of Supervisory Control Theory to Guide Cellular Dynamics

In this paper we propose a theoretical framework, based on the Supervisory Control Theory, to guide the dynamics of genetic regulatory networks. The system to be controlled is abstracted by discrete-event models and the devised supervisor is assumed to be realized as a biological network, that is, it acts autonomously inside the cellular environment. The ideas presented in this paper may be extended to the more general case, where the biological plant encompasses also signaling and metabolic events. The formal synthesis of supervisors to control the behavior of cellular networks has several applications, in fields that range from the optimization of metabolites production to the treatment of diseases, such as cancer.

Living on the edge of chaos: minimally nonlinear models of genetic regulatory dynamics

Linearized catalytic reaction equations (modelling, for example, the dynamics of genetic regulatory networks), under the constraint that expression levels, i.e. molecular concentrations of nucleic material, are positive, exhibit non-trivial dynamical properties, which depend on the average connectivity of the reaction network. In these systems, an inflation of the edge of chaos and multi-stability have been demonstrated to exist. The positivity constraint introduces a nonlinearity, which makes chaotic dynamics possible. Despite the simplicity of such minimally nonlinear systems, their basic properties allow us to understand the fundamental dynamical properties of complex biological reaction networks. We analyse the Lyapunov spectrum, determine the probability of finding stationary oscillating solutions, demonstrate the effect of the nonlinearity on the effective in- and out-degree of the active interaction network, and study how the frequency distributions of oscillatory modes of such a system depend on the average connectivity.

Characteristics of Transcriptional Activity in Nonlinear Dynamics of Genetic Regulatory Networks

Microarray measurements of mRNA abundances is a standard tool for evaluation of transcriptional activity in functional genomics. The methodology underlying these measurements assumes existence of a direct link between transcription levels, that is, gene-specific mRNA copy numbers present in the cell, and transcription rates, that is, the numbers of gene-specific mRNA molecules synthesized per unit of time. In this paper, the question of whether or not such a tight interdependence may exist is examined in the context of nonlinear dynamics of genetic regulatory networks. Using the equations of chemical kinetics, a model has been constructed that is capable of explicitly taking into consideration nonlinear interactions between the genes through the teamwork of transcription factors. Jacobian analysis of stability has shown that steady state equilibrium is impossible in such systems. However, phase space compressibility is found to be negative, thus suggesting that asymptotic stability may exist and assume either the form of limit cycle or of a chaotic attractor. It is argued that in rapidly fluctuating or chaotic systems, direct evaluation of transcription rates through transcription levels is highly problematic. It is also noted that even if a hypothetical steady state did exist, the knowledge of transcription levels alone would not be sufficient for the evaluation of transcription rates; an additional set of parameters, namely the mRNA decay rates, would be required. An overall conclusion of the work is that the measurements of mRNA abundances are not truly representative of the functionality of genes and structural fidelity of the genetic codes.

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.

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.

Stochastic cooperativity in non-linear dynamics of genetic regulatory networks

Two major approaches are known in the field of stochastic dynamics of genetic regulatory networks (GRN). The first one, referred here to as the Markov Process Paradigm (MPP), places the focus of attention on the fact that many biochemical constituents vitally important for the network functionality are present only in small quantities within the cell, and therefore the regulatory process is essentially discrete and prone to relatively big fluctuations. The Master Equation of Markov Processes is an appropriate tool for the description of this kind of stochasticity. The second approach, the Non-linear Dynamics Paradigm (NDP), treats the regulatory process as essentially continuous. A natural tool for the description of such processes are deterministic differential equations. According to NDP, stochasticity in such systems occurs due to possible bistability and oscillatory motion within the limit cycles. The goal of this paper is to outline a third scenario of stochasticity in the regulatory process. This scenario is only conceivable in high-dimensional, highly non-linear systems, and thus represents an adequate framework for conceptually modeling the GRN. We refer to this framework as the Stochastic Cooperativity Paradigm (SCP). In this approach, the focus of attention is placed on the fact that in systems with the size and link density of GRN (∼25 000 and ∼100, respectively), the confluence of all the factors which are necessary for gene expression is a comparatively rare event, and only massive redundancy makes such events sufficiently frequent. An immediate consequence of this rareness is ‘burstiness’ in mRNA and protein concentrations, a well known effect in intracellular dynamics. We demonstrate that a high-dimensional non-linear system, despite the absence of explicit mechanisms for suppressing inherent instability, may nevertheless reside in a state of stationary pseudo-random fluctuations which for all practical purposes may be regarded as a stochastic process. This type of stochastic behavior is an inherent property of such systems and requires neither an external random force as in the Langevin approach, nor the discreteness of the process as in MPP, nor highly specialized conditions of bistability as in NDP, nor bifurcations with transition to chaos as in low-dimensional chaotic maps.

Transient Dynamics of Genetic Regulatory Networks

We present an approximation scheme for deriving reaction rate equations of genetic regulatory networks. This scheme predicts the timescales of transient dynamics of such networks more accurately than does standard quasi-steady state analysis by introducing prefactors to the ODEs that govern the dynamics of the protein concentrations. These prefactors render the ODE systems slower than their quasi-steady state approximation counterparts. We introduce the method by examining a positive feedback gene regulatory network, and show how the transient dynamics of this network are more accurately modeled when the prefactor is included. Next, we examine the repressilator, a genetic oscillator, and show that the period, amplitude, and bifurcation diagram defining the onset of the oscillations are better estimated by the prefactor method. Finally, we examine the consequences of the method to the dynamics of reduced models of the phage lambda switch, and show that the switching times between the two states is slowed by the presence of the prefactor that arises from protein multimerization and DNA binding.

Boolean dynamics of genetic regulatory networks inferred from microarray time series data

Methods available for the inference of genetic regulatory networks strive to produce a single network, usually by optimizing some quantity to fit the experimental observations. In this article we investigate the possibility that multiple networks can be inferred, all resulting in similar dynamics. This idea is motivated by theoretical work which suggests that biological networks are robust and adaptable to change, and that the overall behavior of a genetic regulatory network might be captured in terms of dynamical basins of attraction. We have developed and implemented a method for inferring genetic regulatory networks for time series microarray data. Our method first clusters and discretizes the gene expression data using k-means and support vector regression. We then enumerate Boolean activation-inhibition networks to match the discretized data. Finally, the dynamics of the Boolean networks are examined. We have tested our method on two immunology microarray datasets: an IL-2-stimulated T cell response dataset and a LPS-stimulated macrophage response dataset. In both cases, we discovered that many networks matched the data, and that most of these networks had similar dynamics. Supplementary data are available at Bioinformatics online.

Simulation study in Probabilistic Boolean Network models for genetic regulatory networks

Probabilistic Boolean Network (PBN) is widely used to model genetic regulatory networks. Evolution of the PBN is according to the transition probability matrix. Steady-state (long-run behaviour) analysis is a key aspect in studying the dynamics of genetic regulatory networks. In this paper, an efficient method to construct the sparse transition probability matrix is proposed, and the power method based on the sparse matrix-vector multiplication is applied to compute the steady-state probability distribution. Such methods provide a tool for us to study the sensitivity of the steady-state distribution to the influence of input genes, gene connections and Boolean networks. Simulation results based on a real network are given to illustrate the method and to demonstrate the steady-state analysis.

Stochastic Oscillations in Genetic Regulatory Networks: Application to Microarray Experiments

We analyze the stochastic dynamics of genetic regulatory networks using a system of nonlinear differential equations. The system of S-functions is applied to capture the role of RNA polymerase in the transcription-translation mechanism. Using probabilistic properties of chemical rate equations, we derive a system of stochastic differential equations which are analytically tractable despite the high dimension of the regulatory network. Using stationary solutions of these equations, we explain the apparently paradoxical results of some recent time-course microarray experiments where mRNA transcription levels are found to only weakly correlate with the corresponding transcription rates. Combining analytical and simulation approaches, we determine the set of relationships between the size of the regulatory network, its structural complexity, chemical variability, and spectrum of oscillations. In particular, we show that temporal variability of chemical constituents may decrease while complexity of the network is increasing. This finding provides an insight into the nature of "functional determinism" of such an inherently stochastic system as genetic regulatory network.

GeneVis: Simulation and Visualization of Genetic Networks

GeneVis simulates genetic networks and visualizes the process of this simulation interactively, providing a visual environment for exploring the dynamics of genetic regulatory networks. The visualization environment supports several representational modes, which include: an individual protein representation, a protein concentration representation, and a network structure representation. The individual protein representation shows the activities of the individual proteins. The protein concentration representation illustrates the relative spread and concentrations of the different proteins in the simulation. The network structure representation depicts the genetic network dependencies that are present in the simulation. GeneVis includes several interactive viewing tools. These include animated transitions from the individual protein representation to the protein concentration representation and from the individual protein representation to the network structure representation. Three types of lenses are used to provide different views within a representation: fuzzy lenses, base pair lenses, and the network structure ring lens. With a fuzzy lens an alternate representation can be viewed in a selected region. The base pair lenses allow users to reposition genes for better viewing or to minimize interference during the simulation. The ring lens provides detail-in-context viewing of individual levels in the genetic network structure representation.

Genexp--a genetic network simulation environment.

An environment for simulation of dynamics of genetic regulatory networks is presented. The model is based on the recurrent neural network principle and allows to interactively simulate various genetic regulatory interactions under different features of the system. The results are displayed graphically. http://proteom.biomed.cas.cz/genexp

Genetic control of flower morphogenesis in Arabidopsis thaliana: a logical analysis.

A large number of molecular mechanisms at the basis of gene regulation have been described during the last few decades. It is now becoming possible to address questions dealing with both the structure and the dynamics of genetic regulatory networks, at least in the case of some of the best-characterized organisms. Most recent attempts to address these questions deal with microbial or animal model systems. In contrast, we analyze here a gene network involved in the control of the morphogenesis of flowers in a model plant, Arabidopsis thaliana. The genetic control of flower morphogenesis in Arabidopsis involves a large number of genes, of which 10 are considered here. The network topology has been derived from published genetic and molecular data, mainly relying on mRNA expression patterns under wild-type and mutant backgrounds. Using a 'generalized logical formalism', we provide a qualitative model and derive the parameter constraints accounting for the different patterns of gene expression found in the four floral organs of Arabidopsis (sepals, petals, stamens and carpels), plus a 'non-floral' state. This model also allows the simulation or the prediction of various mutant phenotypes. On the basis of our model analysis, we predict the existence of a sixth stable pattern of gene expression, yet to be characterized experimentally. Moreover, our dynamical analysis leads to the prediction of at least one more regulator of the gene LFY, likely to be involved in the transition from the non-flowering state to the flowering pathways. Finally, this work, together with other theoretical and experimental considerations, leads us to propose some general conclusions about the structure of gene networks controlling development.