Nested canalyzing depth and network stability

We introduce the nested canalyzing depth of a function, which measures the extent to which it retains a nested canalyzing structure. We characterize the structure of functions with a given depth and compute the expected activities and sensitivities of the variables. This analysis quantifies how canalyzation leads to higher stability in Boolean networks. It generalizes the notion of nested canalyzing functions (NCFs), which are precisely the functions with maximum depth. NCFs have been proposed as gene regulatory network models, but their structure is frequently too restrictive and they are extremely sparse. We find that functions become decreasingly sensitive to input perturbations as the canalyzing depth increases, but exhibit rapidly diminishing returns in stability. Additionally, we show that as depth increases, the dynamics of networks using these functions quickly approach the critical regime, suggesting that real networks exhibit some degree of canalyzing depth, and that NCFs are not significantly better than functions of sufficient depth for many applications of the modeling and reverse engineering of biological networks.Comment: 13 pages, 2 figure

Robustness of Transcriptional Regulation in Yeast-like Model Boolean Networks

We investigate the dynamical properties of the transcriptional regulation of gene expression in the yeast Saccharomyces Cerevisiae within the framework of a synchronously and deterministically updated Boolean network model. By means of a dynamically determinant subnetwork, we explore the robustness of transcriptional regulation as a function of the type of Boolean functions used in the model that mimic the influence of regulating agents on the transcription level of a gene. We compare the results obtained for the actual yeast network with those from two different model networks, one with similar in-degree distribution as the yeast and random otherwise, and another due to Balcan et al., where the global topology of the yeast network is reproduced faithfully. We, surprisingly, find that the first set of model networks better reproduce the results found with the actual yeast network, even though the Balcan et al. model networks are structurally more similar to that of yeast.Comment: 7 pages, 4 figures, To appear in Int. J. Bifurcation and Chaos, typos were corrected and 2 references were adde

Inferring Biologically Relevant Models: Nested Canalyzing Functions

Inferring dynamic biochemical networks is one of the main challenges in systems biology. Given experimental data, the objective is to identify the rules of interaction among the different entities of the network. However, the number of possible models fitting the available data is huge and identifying a biologically relevant model is of great interest. Nested canalyzing functions, where variables in a given order dominate the function, have recently been proposed as a framework for modeling gene regulatory networks. Previously we described this class of functions as an algebraic toric variety. In this paper, we present an algorithm that identifies all nested canalyzing models that fit the given data. We demonstrate our methods using a well-known Boolean model of the cell cycle in budding yeast

Mutual information in random Boolean models of regulatory networks

The amount of mutual information contained in time series of two elements gives a measure of how well their activities are coordinated. In a large, complex network of interacting elements, such as a genetic regulatory network within a cell, the average of the mutual information over all pairs is a global measure of how well the system can coordinate its internal dynamics. We study this average pairwise mutual information in random Boolean networks (RBNs) as a function of the distribution of Boolean rules implemented at each element, assuming that the links in the network are randomly placed. Efficient numerical methods for calculating show that as the number of network nodes N approaches infinity, the quantity N exhibits a discontinuity at parameter values corresponding to critical RBNs. For finite systems it peaks near the critical value, but slightly in the disordered regime for typical parameter variations. The source of high values of N is the indirect correlations between pairs of elements from different long chains with a common starting point. The contribution from pairs that are directly linked approaches zero for critical networks and peaks deep in the disordered regime.Comment: 11 pages, 6 figures; Minor revisions for clarity and figure format, one reference adde

Random Boolean Network Models and the Yeast Transcriptional Network

The recently measured yeast transcriptional network is analyzed in terms of simplified Boolean network models, with the aim of determining feasible rule structures, given the requirement of stable solutions of the generated Boolean networks. We find that for ensembles of generated models, those with canalyzing Boolean rules are remarkably stable, whereas those with random Boolean rules are only marginally stable. Furthermore, substantial parts of the generated networks are frozen, in the sense that they reach the same state regardless of initial state. Thus, our ensemble approach suggests that the yeast network shows highly ordered dynamics.Comment: 23 pages, 5 figure

Relative Stability of Network States in Boolean Network Models of Gene Regulation in Development

Progress in cell type reprogramming has revived the interest in Waddington's concept of the epigenetic landscape. Recently researchers developed the quasi-potential theory to represent the Waddington's landscape. The Quasi-potential U(x), derived from interactions in the gene regulatory network (GRN) of a cell, quantifies the relative stability of network states, which determine the effort required for state transitions in a multi-stable dynamical system. However, quasi-potential landscapes, originally developed for continuous systems, are not suitable for discrete-valued networks which are important tools to study complex systems. In this paper, we provide a framework to quantify the landscape for discrete Boolean networks (BNs). We apply our framework to study pancreas cell differentiation where an ensemble of BN models is considered based on the structure of a minimal GRN for pancreas development. We impose biologically motivated structural constraints (corresponding to specific type of Boolean functions) and dynamical constraints (corresponding to stable attractor states) to limit the space of BN models for pancreas development. In addition, we enforce a novel functional constraint corresponding to the relative ordering of attractor states in BN models to restrict the space of BN models to the biological relevant class. We find that BNs with canalyzing/sign-compatible Boolean functions best capture the dynamics of pancreas cell differentiation. This framework can also determine the genes' influence on cell state transitions, and thus can facilitate the rational design of cell reprogramming protocols.Comment: 24 pages, 6 figures, 1 tabl