Methods of modeling cellular regulatory networks as diverse as differential equations and Boolean networks co-exist, however, without any closer correspondence to each other. With the example system of the fission yeast cell cycle control network, we here set the two approaches in relation to each other. We find that the Boolean network can be formulated as a specific coarse-grained limit of the more detailed differential network model for this system. This lays the mathematical foundation on which Boolean networks can be applied to biological regulatory networks in a controlled way.
Logical models have been successfully used to describe regulatory and signaling networks without requiring quantitative data. However, existing data is insufficient to adequately define a unique model, rendering the parametrization of a given model a difficult task. Here, we focus on the characterization of the set of Boolean functions compatible with a given regulatory structure, i.e. the set of all monotone nondegenerate Boolean functions. We then propose an original set of rules to locally explore the direct neighboring functions of any function in this set, without explicitly generating th…
The time taken for gene expression varies not least because proteins vary in length considerably. This paper uses an abstract, tuneable Boolean regulatory network model to explore gene expression time variation. In particular, it is shown how non-uniform expression times can emerge under certain conditions through simulated evolution. That is, gene expression time variance appears beneficial in the shaping of the dynamical behaviour of the regulatory network without explicit consideration of protein function.
Random Boolean networks have been used widely to explore aspects of gene regulatory networks. A modified form of the model through which to systematically explore the effects of increasing the number of gene states has previously been introduced. In this paper, these discrete dynamical networks are coevolved within coupled, rugged fitness landscapes to explore their behaviour. Results suggest the general properties of the Boolean model remain with higher valued logic regardless of the update scheme or fitness sampling method. Introducing topological asymmetry in the coevolving networks is seen…
The significant role of epigenetic mechanisms within natural systems has become increasingly clear. This paper uses a recently presented abstract, tunable Boolean genetic regulatory network model to explore aspects of epigenetics. It is shown how dynamically controlling transcription via a DNA methylation-inspired mechanism can be selected for by simulated evolution under various single and multiple cell scenarios. Further, it is shown that the effects of such control can be inherited without detriment to fitness.
As a discrete approach to genetic regulatory networks, Boolean models provide an essential qualitative description of the structure of interactions among genes and proteins. Boolean models generally assume only two possible states (expressed or not expressed) for each gene or protein in the network as well as a high level of synchronization among the various regulatory processes. In this paper, we discuss and compare two possible methods of adapting qualitative models to incorporate the continuous-time character of regulatory networks. The first method consists of introducing asynchronous upda…
Interactions between genes and gene products give rise to complex circuits that enable cells to process information and respond to external signals. Theoretical studies often describe these interactions using continuous, stochastic, or logical approaches. We propose a new modeling framework for gene regulatory networks, that combines the intuitive appeal of a qualitative description of gene states with a high flexibility in incorporating stochasticity in the duration of cellular processes. We apply our methods to the regulatory network of the segment polarity genes, thus gaining novel insights…
A Boolean network model of the cell-cycle regulatory network of fission yeast (Schizosaccharomyces Pombe) is constructed solely on the basis of the known biochemical interaction topology. Simulating the model in the computer, faithfully reproduces the known sequence of regulatory activity patterns along the cell cycle of the living cell. Contrary to existing differential equation models, no parameters enter the model except the structure of the regulatory circuitry. The dynamical properties of the model indicate that the biological dynamical sequence is robustly implemented in the regulatory n…
We propose new activity-dependent adaptive Boolean networks inspired by the cis-regulatory mechanism in gene regulatory networks. We analytically show that our model can be solved for stationary in-degree distribution for a wide class of update rules by employing the annealed approximation of Boolean network dynamics and that evolved Boolean networks have a preassigned average sensitivity that can be set independently of update rules if certain conditions are satisfied. In particular, when it is set to 1, our theory predicts that the proposed network rewiring algorithm drives Boolean networks …
Background. Dynamical models of gene regulatory networks (GRNs) are highly effective in describing complex biological phenomena and processes, such as cell differentiation and cancer development. Yet, the topological and functional characterization of real GRNs is often still partial and an exhaustive picture of their functioning is missing. Motivation. We here introduce CABeRNET, a Cytoscape app for the generation, simulation and analysis of Boolean models of GRNs, specifically focused on their augmentation when a only partial topological and functional characterization of the network is avai…
Gene regulatory networks can be successfully modeled as Boolean networks. A much discussed hypothesis says that such model networks reproduce empirical findings the best if they are tuned to operate at criticality, i.e. at the borderline between their ordered and disordered phases. Critical networks have been argued to lead to a number of functional advantages such as maximal dynamical range, maximal sensitivity to environmental changes, as well as to an excellent trade off between stability and flexibility. Here, we study the effect of noise within the context of Boolean networks trained to l…
Gene regulatory network (GRN) modeling is a well-established theoretical framework for the study of cell-fate specification during developmental processes. Recently, dynamical models of GRNs have been taken as a basis for formalizing the metaphorical model of Waddington's epigenetic landscape, providing a natural extension for the general protocol of GRN modeling. In this contribution we present in a coherent framework a novel implementation of two previously proposed general frameworks for modeling the Epigenetic Attractors Landscape associated with boolean GRNs: the inter-attractor and inter…
Boolean networks have been successfully used in modelling gene regulatory networks. In this paper we propose a reduction method that reduces the complexity of a Boolean network but keeps dynamical properties and topological features and hence it makes the analysis easier; as a result, it allows for a better understanding of the role of network topology on the dynamics. In particular, we use the reduction method to study steady states of Boolean models.
One of the characteristic features of genetic networks is their inherent robustness, that is, their ability to retain functionality in spite of the introduction of random errors. In this paper, we seek to better understand how robustness is achieved and what functionalities can be maintained robustly. Our goal is to formalize some of the language used in biological discussions in a reasonable mathematical framework, where questions can be answered in a rigorous fashion. These results provide basic conceptual understanding of robust regulatory networks that should be valuable independent of the…
Boolean networks are popular tools for the exploration of qualitative dynamical properties of biological systems. Several dynamical interpretations have been proposed based on the same logical structure that captures the interactions between Boolean components. They reproduce, in different degrees, the behaviours emerging in more quantitative models. In particular, regulatory conflicts can prevent the standard asynchronous dynamics from reproducing some trajectories that might be expected upon inspection of more detailed models. We introduce and study the class of networks with linear cuts, wh…
The determination and classification of fixed points of large Boolean networks is addressed in terms of constraint satisfaction problem. We develop a general simplification scheme that, removing all those variables and functions belonging to trivial logical cascades, returns the computational core of the network. The onset of an easy-to-complex regulatory phase is introduced as a function of the parameters of the model, identifying both theoretically and algorithmically the relevant regulatory variables.
Elucidating the architecture and dynamics of large scale genetic regulatory networks of cells is an important goal in systems biology. We study the system level dynamical properties of the genetic network of Escherichia coli that regulates its metabolism, and show how its design leads to biologically useful cellular properties. Our study uses the database (Covert et al., Nature 2004) containing 583 genes and 96 external metabolites which describes not only the network connections but also the boolean rule at each gene node that controls the switching on or off of the gene as a function of its …
Random Boolean networks (RBNs) have been a popular model of genetic regulatory networks for more than four decades. However, most RBN studies have been made with random topologies, while real regulatory networks have been found to be modular. In this work, we extend classical RBNs to define modular RBNs. Statistical experiments and analytical results show that modularity has a strong effect on the properties of RBNs. In particular, modular RBNs have more attractors and are closer to criticality when chaotic dynamics would be expected, compared to classical RBNs.
The co-evolution of network topology and dynamics is studied in an evolutionary Boolean network model that is a simple model of gene regulatory network. We find that a critical state emerges spontaneously resulting from interplay between topology and dynamics during the evolution. The final evolved state is shown to be independent of initial conditions. The network appears to be driven to a random Boolean network with uniform in-degree of two in the large network limit. However, for biologically realized network sizes, significant finite-size effects are observed including a broad in-degree di…
Recent progress in experimental techniques has enabled us to quantitatively study stochastic and flexible behavior of biological systems. For example, gene regulatory networks perform stochastic information processing and their functionalities have been extensively studied. In gene regulatory networks, there are specific subgraphs called network motifs that occur at frequencies much higher than those found in randomized networks. Further understanding of the designing principle of such networks is highly desirable. In a different context, information thermodynamics has been developed as a theo…
Computational models of biological processes provide one of the most powerful methods for a detailed analysis of the mechanisms that drive the behavior of complex systems. Logic-based modeling has enhanced our understanding and interpretation of those systems. Defining rules that determine how the output activity of biological entities is regulated by their respective inputs has proven to be challenging, due to increasingly larger models and the presence of noise in data, allowing multiple model parameterizations to fit the experimental observations. We present several Boolean function metrics…
This paper proposes a new method to reverse engineer gene regulatory networks from experimental data. The modeling framework used is time-discrete deterministic dynamical systems, with a finite set of states for each of the variables. The simplest examples of such models are Boolean networks, in which variables have only two possible states. The use of a larger number of possible states allows a finer discretization of experimental data and more than one possible mode of action for the variables, depending on threshold values. Furthermore, with a suitable choice of state set, one can employ po…
Gene regulatory networks (GRNs) are increasingly used for explaining biological processes with complex transcriptional regulation. A GRN links the expression levels of a set of genes via regulatory controls that gene products exert on one another. Boolean networks are a common modeling choice since they balance between detail and ease of analysis. However, even for Boolean networks the problem of fitting a given network model to an expression dataset is NP-Complete. Previous methods have addressed this issue heuristically or by focusing on acyclic networks and specific classes of regulation fu…
Recent experimental advances in biology allow researchers to obtain gene expression profiles at single-cell resolution over hundreds, or even thousands of cells at once. These single-cell measurements provide snapshots of the states of the cells that make up a tissue, instead of the population-level averages provided by conventional high-throughput experiments. This new data therefore provides an exciting opportunity for computational modelling. In this paper we introduce the idea of viewing single-cell gene expression profiles as states of an asynchronous Boolean network, and frame model infe…
In this paper, we analyse large random Boolean networks in terms of a constraint satisfaction problem. We first develop an algorithmic scheme which allows to prune simple logical cascades and under-determined variables, returning thereby the computational core of the network. Second we apply the cavity method to analyse number and organisation of fixed points. We find in particular a phase transition between an easy and a complex regulatory phase, the latter one being characterised by the existence of an exponential number of macroscopically separated fixed-point clusters. The different techni…
Boolean networks are a popular modeling framework in computational biology to capture the dynamics of molecular networks, such as gene regulatory networks. It has been observed that many published models of such networks are defined by regulatory rules driving the dynamics that have certain so-called canalizing properties. In this paper, we investigate the dynamics of a random Boolean network with such properties using analytical methods and simulations. From our simulations, we observe that Boolean networks with higher canalizing depth have generally fewer attractors, the attractors are small…
The problem of reliability of the dynamics in biological regulatory networks is studied in the framework of a generalized Boolean network model with continuous timing and noise. Using well-known artificial genetic networks such as the repressilator, we discuss concepts of reliability of rhythmic attractors. In a simple evolution process we investigate how overall network structure affects the reliability of the dynamics. In the course of the evolution, networks are selected for reliable dynamics. We find that most networks can be easily evolved towards reliable functioning while preserving the…
The editing of transcribed RNA by other molecules such that the form of the final product differs from that specified in the corresponding DNA sequence is ubiquitous. This paper uses an abstract, tunable Boolean genetic regulatory network model to explore aspects of RNA editing. In particular, it is shown how dynamically altering expressed sequences via a guide RNA-inspired mechanism can be selected for by simulated evolution under various single and multicellular scenarios.
Control problem in a biological system is the problem of finding an interventional policy for changing the state of the biological system from an undesirable state, e.g. disease, into a desirable healthy state. Boolean networks are utilized as mathematical model for gene regulatory networks. This paper provides an algorithm to solve the control problem in Boolean networks. The proposed algorithm is implemented and applied on two biological systems: T-cell receptor network and Drosophila melanogaster network. Results show that the proposed algorithm works faster in solving the control problem o…
This thesis aims at the logical analysis of discrete processes, in particular of such generated by gene regulatory networks. States, transitions and operators from temporal logics are expressed in the language of Formal Concept Analysis. By the attribute exploration algorithm, an expert or a computer program is enabled to validate a minimal and complete set of implications, e.g. by comparison of predictions derived from literature with observed data. Here, these rules represent temporal dependencies within gene regulatory networks including coexpression of genes, reachability of states, invari…
Module network inference is a statistical method to reconstruct gene regulatory networks, which uses probabilistic graphical models to learn modules of coregulated genes and their upstream regulatory programs from genome-wide gene expression and other omics data. Here we review the basic theory of module network inference, present protocols for common gene regulatory network reconstruction scenarios based on the Lemon-Tree software, and show, using human gene expression data, how the software can also be applied to learn differential module networks across multiple experimental conditions.
The complex dynamics of gene expression in living cells can be well-approximated using Boolean networks. The average sensitivity is a natural measure of stability in these systems: values below one indicate typically stable dynamics associated with an ordered phase, whereas values above one indicate chaotic dynamics. This yields a theoretically motivated adaptive advantage to being near the critical value of one, at the boundary between order and chaos. Here, we measure average sensitivity for 66 publicly available Boolean network models describing the function of gene regulatory circuits acro…
We investigate the structural and dynamical properties of the transcriptional regulatory network of the yeast {\it Saccharomyces cerevisiae} and compare it with two unbiased ensembles: one obtained by reshuffling the edges and the other generated by mimicking the transcriptional regulation mechanism within the cell. Both ensembles reproduce the degree distributions (the first -by construction- exactly and the second approximately), degree-degree correlations and the $k$-core structure observed in Yeast. An exceptionally large dynamically relevant core network found in Yeast in comparison with …
Regulatory dynamics in biology is often described by continuous rate equations for continuously varying chemical concentrations. Binary discretization of state space and time leads to Boolean dynamics. In the latter, the dynamics has been called unstable if flip perturbations lead to damage spreading. Here we find that this stability classification strongly differs from the stability properties of the original continuous dynamics under small perturbations of the state vector. In particular, random networks of nodes with large sensitivity yield stable dynamics under small perturbations.
This paper uses a recently presented abstract, tuneable Boolean regulatory network model extended to consider aspects of mobile DNA, such as transposons. The significant role of mobile DNA in the evolution of natural systems is becoming increasingly clear. This paper shows how dynamically controlling network node connectivity and function via transposon-inspired mechanisms can be selected for in computational intelligence tasks to give improved performance. The designs of dynamical networks intended for implementation within the slime mould Physarum polycephalum and for the distributed control…
This short paper presents an abstract, tunable model of genomic structural change within the cell lifecycle and explores its use with simulated evolution. A well-known Boolean model of genetic regulatory networks is extended to include changes in node connectivity based upon the current cell state, e.g., via transposable elements. The underlying behaviour of the resulting dynamical networks is investigated before their evolvability is explored using a version of the NK model of fitness landscapes. Structural dynamism is found to be selected for in non-stationary environments and subsequently s…
Many biological systems, such as metabolic pathways, exhibit bistability behavior: these biological systems exhibit two distinct stable states with switching between the two stable states controlled by certain conditions. Since understanding bistability is key for understanding these biological systems, mathematical modeling of the bistability phenomenon has been at the focus of researches in quantitative and system biology. Recent study shows that Boolean networks offer relative simple mathematical models that are capable of capturing these essential information. Thus a better understanding o…
We present BoolSi, an open-source cross-platform command line tool for distributed simulations of deterministic Boolean networks with synchronous update. It uses MPI standard to support execution on computational clusters, as well as parallel processing on a single computer. BoolSi can be used to model the behavior of complex dynamic networks, such as gene regulatory networks. In particular, it allows for identification and statistical analysis of network attractors. We perform a case study of the activity of a cambium cell to demonstrate the capabilities of the tool.
Boolean threshold networks have recently been proposed as useful tools to model the dynamics of genetic regulatory networks, and have been successfully applied to describe the cell cycles of \textit{S. cerevisiae} and \textit{S. pombe}. Threshold networks assume that gene regulation processes are additive. This, however, contrasts with the mechanism proposed by S. Kauffman in which each of the logic functions must be carefully constructed to accurately take into account the combinatorial nature of gene regulation. While Kauffman Boolean networks have been extensively studied and proved to have…
Random Boolean networks (RBNs) are frequently employed for modelling complex systems driven by information processing, e.g. for gene regulatory networks (GRNs). Here we propose a hierarchical adaptive RBN (HARBN) as a system consisting of distinct adaptive RBNs - subnetworks - connected by a set of permanent interlinks. Information measures and internal subnetworks topology of HARBN coevolve and reach steady-states that are specific for a given network structure. We investigate mean node information, mean edge information as well as a mean node degree as functions of model parameters and demon…
Boolean networks with canalizing functions are used to model gene regulatory networks. In order to learn how such networks may behave under evolutionary forces, we simulate the evolution of a single Boolean network by means of an adaptive walk, which allows us to explore the fitness landscape. Mutations change the connections and the functions of the nodes. Our fitness criterion is the robustness of the dynamical attractors against small perturbations. We find that with this fitness criterion the global maximum is always reached and that there is a huge neutral space of 100% fitness. Furthermo…
The global dynamics of gene regulatory networks are known to show robustness to perturbations in the form of intrinsic and extrinsic noise, as well as mutations of individual genes. One molecular mechanism underlying this robustness has been identified as the action of so-called microRNAs that operate via feedforward loops. We present results of a computational study, using the modeling framework of stochastic Boolean networks, which explores the role that such network motifs play in stabilizing global dynamics. The paper introduces a new measure for the stability of stochastic networks. The r…
Consider a large Boolean network with a feed forward structure. Given a probability distribution on the inputs, can one find, possibly small, collections of input nodes that determine the states of most other nodes in the network? To answer this question, a notion that quantifies the determinative power of an input over the states of the nodes in the network is needed. We argue that the mutual information (MI) between a given subset of the inputs X = {X_1, ..., X_n} of some node i and its associated function f_i(X) quantifies the determinative power of this set of inputs over node i. We compar…
Understanding design principles of molecular interaction networks is an important goal of molecular systems biology. Some insights have been gained into features of their network topology through the discovery of graph theoretic patterns that constrain network dynamics. This paper contributes to the identification of patterns in the mechanisms that govern network dynamics. The control of nodes in gene regulatory, signaling, and metabolic networks is governed by a variety of biochemical mechanisms, with inputs from other network nodes that act additively or synergistically. This paper focuses o…
Diverse biological networks exhibit universal features distinguished from those of random networks, calling much attention to their origins and implications. Here we propose a minimal evolution model of Boolean regulatory networks, which evolve by selectively rewiring links towards enhancing adaptability to a changing environment and stability against dynamical perturbations. We find that sparse and heterogeneous connectivity patterns emerge, which show qualitative agreement with real transcriptional regulatory networks and metabolic networks. The characteristic scaling behavior of stability r…
Boolean networks have been the object of much attention, especially since S. Kauffman proposed them in the 1960's as models for gene regulatory networks. These systems are characterized by being defined on a Boolean state space and by simultaneous updating at discrete time steps. Of particular importance for biological applications are networks in which the indegree for each variable is bounded by a fixed constant, as was stressed by Kauffman in his original papers. An important question is which conditions on the network topology can rule out exponentially long periodic orbits in the system. …
Since their introduction, Boolean networks have been traditionally studied in view of their rich dynamical behavior under different update protocols and for their qualitative analogy with cell regulatory networks. More recently, tools borrowed from statistical physics of disordered systems and from computer science have provided a more complete characterization of their equilibrium behavior. However, the largest part of the results have been obtained in the thermodynamic limit, which is often far from being reached when dealing with realistic instances of the problem. The numerical analysis pr…
Families of ODE models characterized by a common sign structure of their Jacobi matrix are investigated within the formalism of qualitative differential equations. In the context of regulatory networks the sign structure of the Jacobi matrix carries the information about which components of the network inhibit or activate each other. Information about constraints on the behavior of models in this family is stored in a so called qualitative state transition graph. We showed previously that a similar approach can be used to analyze a model pool of Boolean functions characterized by a common inte…
