Monostability and multistability of genetic regulatory networks with different types of regulation functions

The official published version of the article can be found at the link below.Monostability and multistability are proven to be two important topics in synthesis biology and system biology. In this paper, both monostability and multistability are analyzed in a unified framework by applying control theory and mathematical tools. The genetic regulatory networks (GRNs) with multiple time-varying delays and different types of regulation functions are considered. By putting forward a general sector-like regulation function and utilizing up-to-date techniques, a novel Lyapunov–Krasovskii functional is introduced for achieving delay dependence to ensure less conservatism. A new condition is then proposed for the general stability of a GRN in the form of linear matrix inequalities (LMIs) that are dependent on the upper and lower bounds of the delays. Our general stability conditions are applicable to several frequently used regulation functions. It is shown that the existing results for monostability of GRNs are special cases of our main results. Five examples are employed to illustrate the applicability and usefulness of the developed theoretical results.This work was supported in part by the Biotechnology and Biological Sciences Research Council (BBSRC) of the U.K. under Grant BB/C506264/1, the Royal Society of the U.K., the National Natural Science Foundation of China under Grants 60504008 and 60804028, the Program for New Century Excellent Talents in Universities of China, and the Alexander von Humboldt Foundation of Germany

On multistability of delayed genetic regulatory networks with multivariable regulation functions

The official published version of the article can be found at the link below.Many genetic regulatory networks (GRNs) have the capacity to reach different stable states. This capacity is defined as multistability which is an important regulation mechanism. Multiple time delays and multivariable regulation functions are usually inevitable in such GRNs. In this paper, multistability of GRNs is analyzed by applying the control theory and mathematical tools. This study is to provide a theoretical tool to facilitate the design of synthetic gene circuit with multistability in the perspective of control theory. By transforming such GRNs into a new and uniform mathematical formulation, we put forward a general sector-like regulation function that is capable of quantifying the regulation effects in a more precise way. By resorting to up-to-date techniques, a novel Lyapunov–Krasovskii functional (LKF) is introduced for achieving delay dependence to ensure less conservatism. New conditions are then proposed to ensure the multistability of a GRN in the form of linear matrix inequalities (LMIs) that are dependent on the delays. Our multistability conditions are applicable to several frequently used regulation functions especially the multivariable ones. Two examples are employed to illustrate the applicability and usefulness of the developed theoretical results.This work was supported in part by the Biotechnology and Biological Sciences Research Council (BBSRC) of the UK under Grants BB/C506264/1 and 100/EGM17735, the Royal Society of the UK, the National Natural Science Foundation of China under Grant 61028008, and the International Science and Technology Cooperation Project of China under Grant 2009DFA32050

Phenotypic Variation and Bistable Switching in Bacteria

Microbial research generally focuses on clonal populations. However, bacterial cells with identical genotypes frequently display different phenotypes under identical conditions. This microbial cell individuality is receiving increasing attention in the literature because of its impact on cellular differentiation, survival under selective conditions, and the interaction of pathogens with their hosts. It is becoming clear that stochasticity in gene expression in conjunction with the architecture of the gene network that underlies the cellular processes can generate phenotypic variation. An important regulatory mechanism is the so-called positive feedback, in which a system reinforces its own response, for instance by stimulating the production of an activator. Bistability is an interesting and relevant phenomenon, in which two distinct subpopulations of cells showing discrete levels of gene expression coexist in a single culture. In this chapter, we address techniques and approaches used to establish phenotypic variation, and relate three well-characterized examples of bistability to the molecular mechanisms that govern these processes, with a focus on positive feedback.

Emergence of switch-like behavior in a large family of simple biochemical networks

Bistability plays a central role in the gene regulatory networks (GRNs) controlling many essential biological functions, including cellular differentiation and cell cycle control. However, establishing the network topologies that can exhibit bistability remains a challenge, in part due to the exceedingly large variety of GRNs that exist for even a small number of components. We begin to address this problem by employing chemical reaction network theory in a comprehensive in silico survey to determine the capacity for bistability of more than 40,000 simple networks that can be formed by two transcription factor-coding genes and their associated proteins (assuming only the most elementary biochemical processes). We find that there exist reaction rate constants leading to bistability in ~90% of these GRN models, including several circuits that do not contain any of the TF cooperativity commonly associated with bistable systems, and the majority of which could only be identified as bistable through an original subnetwork-based analysis. A topological sorting of the two-gene family of networks based on the presence or absence of biochemical reactions reveals eleven minimal bistable networks (i.e., bistable networks that do not contain within them a smaller bistable subnetwork). The large number of previously unknown bistable network topologies suggests that the capacity for switch-like behavior in GRNs arises with relative ease and is not easily lost through network evolution. To highlight the relevance of the systematic application of CRNT to bistable network identification in real biological systems, we integrated publicly available protein-protein interaction, protein-DNA interaction, and gene expression data from Saccharomyces cerevisiae, and identified several GRNs predicted to behave in a bistable fashion.Comment: accepted to PLoS Computational Biolog