Relating Attractors and Singular Steady States in the Logical Analysis of Bioregulatory Networks
(2007)
In 1973 R. Thomas introduced a logical approach to modeling and analysis of
bioregulatory networks. Given a set of Boolean functions describing the
regulatory interactions, a state transition graph is constructed that captures
the dynamics of the system. In the late eighties, Snoussi and Thomas extended
the original framework by including singular values corresponding to
interaction thresholds. They showed that these are needed for a refined
understanding of the network dynamics.
In this paper, we study systematically singular steady states, which are
characteristic of feedback circuits in the interaction graph, and relate them
to the type, number and cardinality of attractors in the state transition
graph. In particular, we derive sufficient conditions for regulatory networks
to exhibit multistationarity or oscillatory behavior, thus giving a partial
converse to the well-known Thomas conjectures.
Based on the logical description of gene regulatory networks developed by R. Thomas, we introduce an enhanced modelling approach that uses timed automata. It yields a refined qualitative description of the dynamics of the system incorporating information not only on ratios of kinetic constants related to synthesis and decay, but also on the time delays occurring in the operations of the system. We demonstrate the potential of our approach by analysing an illustrative gene regulatory network of bacteriophage lambda.
In the well-known discrete modeling framework developed by R. Thomas, the structure of a biological regulatory network is captured in an interaction graph, which, together with a set of Boolean parameters, gives rise to a state transition graph describing all possible dynamical behaviors. For complex networks the analysis of the dynamics becomes more and more difficult, and efficient methods to carry out the analysis are needed. In this paper, we focus on identifying subnetworks of the system that govern the behavior of the system as a whole. We present methods to derive trajectories and attractors of the network from the dynamics suitable subnetworks display in isolation. In addition, we use these ideas to link the existence of certain structural motifs, namely circuits, in the interaction graph to the character and number of attractors in the state transition graph, generalizing and refining results presented in \cite{AB07}. Lastly, we show for a specific class of networks that all possible asymptotic behaviors of networks in that class can be derived from the dynamics of easily identifiable subnetworks.
Boolean modeling frameworks have long since proved their worth for capturing and analyzing essential characteristics of complex systems.
Hybrid approaches aim at exploiting the advantages of Boolean formalisms while refining expressiveness. In this paper, we present a formalism that augments Boolean models with stochastic aspects. More specifically, biological reactions effecting a system in a given state are associated
with probabilities, resulting in dynamical behavior represented as a Markov chain. Using this approach, we model and analyze the cytokinin
response network of Arabidopsis thaliana with a focus on clarifying the character of an important feedback mechanism.
Logical modeling of biological regulatory networks gives rise to a representation of the system's dynamics as a so-called state transition graph. Analysis of such a graph in its entirety allows for a comprehensive understanding of the functionalities and behavior of the modeled system. However, the size of the vertex set of the graph is exponential in the number of the network components making analysis costly, motivating development of reduction methods. In this paper, we present results allowing for a complete description of an asynchronous state transition graph of a Thomas network solely based on the analysis of the subgraph induced by certain extremal states. Utilizing this notion, we compare the behavior of a simple multi-valued network and a corresponding Boolean network and analyze the conservation of dynamical properties between them. Understanding the relation between such coarser and finer models is a necessary step towards meaningful network reduction as well as model refinement methods.
Mathematical modeling often helps to provide a systems perspective on gene regulatory networks. In particular, qualitative approaches are useful when detailed kinetic information is lacking. Multiple methods have been developed that implement qualitative information in different ways, e.g., in purely discrete or hybrid discrete/continuous models. In this paper, we compare the discrete asynchronous logical modeling formalism for gene regulatory networks due to R. Thomas with piecewise affine differential equation models.
We provide a local characterization of the qualitative dynamics of a piecewise affine differential equation model using the discrete dynamics of a corresponding Thomas model. Based on this result, we investigate the consistency of higher-level dynamical properties such as attractor characteristics and reachability. We show that although the two approaches are based on equivalent information, the resulting qualitative dynamics are different. In particular, the dynamics of the piecewise affine differential equation model is not a simple refinement of the dynamics of the Thomas model.
For modeling and analyzing regulatory networks based on qualitative information and possibly additional temporal constraints, approaches using hybrid automata can be very helpful. The formalism focussed on in this paper starts from the logical description developed by R. Thomas to capture network structure and qualitative behavior of a system. Using the framework of timed automata, the analysis of the dynamics can be refined by adding a continuous time evolution. This allows for the incorporation of data on time delays associated with specific processes. In general, structural aspects such as character and strength of interactions as well as time delays are context sensitive in the sense that they depend on the current state of the system. We propose an enhancement of the approach described above, integrating both structural and temporal context sensitivity.
Starting from the logical description of gene regulatory networks developed by R.~Thomas, we introduce an enhanced modelling approach
based on timed automata. We obtain a refined qualitative description of the dynamical behaviour by exploiting not only information on ratios of kinetic parameters related to synthesis and decay, but also constraints on the time delays associated with the operations of the system. We develop a formal framework for handling such temporal constraints using timed automata, discuss the relationship with the original Thomas formalism, and demonstrate the potential of our approach by analysing an illustrative gene regulatory network of bacteriophage~$\lambda$.
A well-known discrete approach to modeling biological regulatory networks is the logical framework developed by R. Thomas. The network structure is captured in an interaction graph, which, together with a set of Boolean parameters, gives rise to a state transition graph describing the dynamical behavior. Together with E. H. Snoussi, Thomas later extended the framework by including singular values representing the threshold values of interactions. A systematic approach was taken in \cite{AB07} to link circuits in the interaction graph with character and number of attractors in the state transition graph by using the information inherent in singular steady states. In this paper, we employ the concept of local interaction graphs to strengthen the results in \cite{AB07}. Using the local interaction graph of a singular steady state, we are able to construct attractors of the regulatory network from attractors of certain subnetworks. As a comprehensive generalization of the framework introduced in \cite{AB07}, we
drop constraints concerning the choice of parameter values to include so-called context sensitive networks.
A biological regulatory network can be modeled as a discrete function f that contains all available information on network component interactions. From f we can derive a graph representation of the network structure as well as of the dynamics of the system. In this paper we introduce a method to identify modules of the network that allow us to construct the behavior of f from the dynamics of the modules. Here, it proves useful to distinguish between dynamical and structural modules, and to define network modules combining aspects of both.
As a key concept we establish the notion of symbolic steady state, which basically represents a set of states where the behavior of f is in some sense predictable, and which gives rise to suitable network modules.
We apply the method to a regulatory network involved in T helper cell differentiation.