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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.
We present a new mathematical approach to metabolic pathway analysis, characterizing a metabolic network by minimal metabolic behaviors and the reversible metabolic space. Our method uses an outer description of the steady state flux cone, based on sets of irreversible reactions. This is different from existing approaches, such as elementary flux modes or extreme pathways, which use an inner description, based on sets of generating vectors. The resulting description of the flux cone is much more compact. By focussing on the reversible and irreversible reactions, our approach provides a different view of the network, which may also lead to new biological insights.
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~$\lambda$.
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.
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.
Flux coupling analysis is a method to identify blocked and coupled reactions
in a metabolic network at steady state. We present a new approach to
flux coupling analysis, which uses a minimum set of generators of the steady state
flux cone. Our method does not require to reconfigure the network by splitting
reversible reactions into forward and backward reactions.
By distinguishing different types of reactions (irreversible, pseudo-irreversible,
fully reversible), we show that reaction coupling relationships can only hold
between certain reaction types. Based on this mathematical analysis, we propose
a new algorithm for flux coupling analysis.
Genome-scale metabolic networks are useful tools for achieving a system-level understanding of metabolism. However, due to their large size, analysis of such networks may be difficult and algorithms can be very slow. Therefore, some authors have suggested to analyze subsystems instead of the original genome-scale models.
Flux coupling analysis (FCA) is a well-known method for detecting functionally related reactions in metabolic networks.
In this paper, we study how flux coupling relations may change if we analyze a subsystem instead of the original network. We show mathematically that a pair of fully, partially or directionally coupled reactions may be detected as uncoupled in certain subsystems. Interestingly, this behavior is the opposite of the flux coupling changes that may occur due to missing reactions, or equivalently, deletion of reactions.
Computational experiments suggest that the analysis of plastid (but not mitochondrial) subsystems may significantly influence the results of FCA. Therefore, the results of FCA for subsystems, especially plastid subsystems, should be interpreted with care.
Constraint-based analysis of metabolic networks has become a widely used approach in computational systems biology.
In the simplest form, a metabolic network is represented by a stoichiometric matrix and thermodynamic information on the irreversibility of certain reactions.
Then one studies the set of all steady-state flux vectors satisfying these stoichiometric and thermodynamic constraints.
We introduce a new lattice-theoretic framework for the computational analysis of metabolic networks, which focuses on the support of the flux vectors,
i.e., we consider only the qualitative information whether or not a certain reaction is active, but not its specific flux rate.
Our lattice-theoretic view includes classical metabolic pathway analysis as a special case, but turns out to be much more flexible and general,
with a wide range of possible applications.
We show how important concepts from metabolic pathway analysis, such as blocked reactions, flux coupling, or elementary modes, can be generalized to arbitrary lattice-based models. We develop corresponding general algorithms and present a number of computational results.
The huge number of elementary flux modes (EFM) in genome-scale metabolic networks makes analysis based on elementary flux modes intrinsically difficult. However, it has been shown that the elementary flux modes with optimal yield often contain highly redundant information. The set of optimal-yield elementary flux modes can be compressed using modules. Up to now, this compression was only possible by first enumerating the whole set of all optimal-yield elementary flux modes.
We present a direct method for computing modules of the thermodynamically constrained optimal flux space of a metabolic network. This method can be used to decompose the set of optimal-yield elementary flux modes in a modular way and to speed up their computation. In addition, it provides a new form of coupling information that is not obtained by classical flux coupling analysis. We illustrate our approach on a set of model organisms.
