Publications about 'multistability' |
Articles in journal or book chapters |
In biological processes such as embryonic development, hematopoietic cell differentiation, and the arising of tumor heterogeneity and consequent resistance to therapy, mechanisms of gene activation and deactivation may play a role in the emergence of phenotypically heterogeneous yet genetically identical (clonal) cellular populations. Mathematically, the variability in phenotypes in the absence of genetic variation can be modeled through the existence of multiple metastable attractors in nonlinear systems subject with stochastic switching, each one of them associated to an alternative epigenetic state. An important theoretical and practical question is that of estimating the number and location of these states, as well as their relative probabilities of occurrence. This paper focuses on a rigorous analytic characterization of multiple modes under slow promoter kinetics, which is a feature of epigenetic regulation. It characterizes the stationary distributions of Chemical Master Equations for gene regulatory networks as a mixture of Poisson distributions. As illustrations, the theory is used to tease out the role of cooperative binding in stochastic models in comparison to deterministic models, and applications are given to various model systems, such as toggle switches in isolation or in communicating populations and a trans-differentiation network. |
This is a short expository article describing how the species-reaction graph (SR graph) can be used to analyze both multistability and monotonicity of biochemical networks. |
This note studies the number of positive steady states in biomolecular reactions consisting of activation/deactivation futile cycles, such as those arising from phosphorylations and dephosphorylations at each level of a MAPK cascade. It is shown that: (1) for some parameter ranges, there are at least n+1 (if n is even) or n (if n is odd) steady states; (2) there never are more than 2n-1 steady states (so, for n=2, there are no more than 3 steady states); (3) for parameters near the standard Michaelis-Menten quasi-steady state conditions, there are at most n+1 steady states; and (4) for parameters far from the standard Michaelis-Menten quasi-steady state conditions, there is at most one steady state. |
The theory of monotone dynamical systems has been found very useful in the modeling of some gene, protein, and signaling networks. In monotone systems, every net feedback loop is positive. On the other hand, negative feedback loops are important features of many systems, since they are required for adaptation and precision. This paper shows that, provided that these negative loops act at a comparatively fast time scale, the main dynamical property of (strongly) monotone systems, convergence to steady states, is still valid. An application is worked out to a double-phosphorylation "futile cycle" motif which plays a central role in eukaryotic cell signaling The workis heavily based on Fenichel-Jones geometric singular perturbation theory. |
For feedback loops involving single input, single output monotone systems with well-defined I/O characteristics, a previous paper provided an approach to determining the location and stability of steady states. A result on global convergence for multistable systems followed as a consequence of the technique. The present paper extends the approach to multiple inputs and outputs. A key idea is the introduction of a reduced system which preserves local stability properties. New results characterizing strong monotonicity of feedback loops involving cascades are also presented. |
Multistability is an important recurring theme in cell signaling, of particular relevance to biological systems that switch between discrete states, generate oscillatory responses, or "remember" transitory stimuli. Standard mathematical methods allow the detection of bistability in some very simple feedback systems (systems with one or two proteins or genes that either activate each other or inhibit each other), but realistic depictions of signal transduction networks are invariably much more complex than this. Here we show that for a class of feedback systems of arbitrary order, the stability properties of the system can be deduced mathematically from how the system behaves when feedback is blocked. Provided that this "open loop," feedback-blocked system is monotone and possesses a sigmoidal characteristic, the system is guaranteed to be bistable for some range of feedback strengths. We present a simple graphical method for deducing the stability behavior and bifurcation diagrams for such systems, and illustrate the method with two examples taken from recent experimental studies of bistable systems: a two-variable Cdc2/Wee1 system and a more complicated five-variable MAPK cascade. |
This paper studies the emergence of multi-stability and hysteresis in those systems that arise, under positive feedback, from monotone systems with well-defined steady-state responses. Such feedback configurations appear routinely in several fields of application, and especially in biology. The results are stated in terms of directly checkable conditions which do not involve explicit knowledge of basins of attractions of each equilibria. |
Conference articles |
Cellular reprogramming is traditionally accomplished through an open loop control approach, wherein key transcription factors are injected in cells to steer a gene regulatory network toward a pluripotent state. Recently, a closed loop feedback control strategy was proposed in order to achieve more accurate control. Previous analyses of the controller were based on deterministic models, ignoring the substantial stochasticity in these networks, Here we analyze the Chemical Master Equation for reaction models with and without the feedback controller. We computationally and analytically investigate the performance of the controller in biologically relevant parameter regimes where stochastic effects dictate system dynamics. Our results indicate that the feedback control approach still ensures reprogramming even when analyzed using a stochastic model. |
In the mathematical modeling of cell differentiation, it is common to think of internal states of cells (quanfitied by activation levels of certain genes) as determining different cell types. We study here the "PU.1/GATA-1 circuit" that controls the development of mature blood cells from hematopoietic stem cells (HSCs). We introduce a rigorous chemical reaction network model of the PU.1/GATA-1 circuit, which incorporates current biological knowledge and find that the resulting ODE model of these biomolecular reactions is incapable of exhibiting multistability, contradicting the fact that differentiation networks have, by definition, alternative stable steady states. When considering instead the stochastic version of this chemical network, we analytically construct the stationary distribution, and are able to show that this distribution is indeed capable of admitting a multiplicity of modes. Finally, we study how a judicious choice of system parameters serves to bias the probabilities towards different stationary states. We remark that certain changes in system parameters can be physically implemented by a biological feedback mechanism; tuning this feedback gives extra degrees of freedom that allow one to assign higher likelihood to some cell types over others. |
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