Abstract
BackgroundThe gene regulatory circuit motif in which two opposing fate-determining transcription factors inhibit each other but activate themselves has been used in mathematical models of binary cell fate decisions in multipotent stem or progenitor cells. This simple circuit can generate multistability and explains the symmetric “poised” precursor state in which both factors are present in the cell at equal amounts as well as the resolution of this indeterminate state as the cell commits to either cell fate characterized by an asymmetric expression pattern of the two factors. This establishes the two alternative stable attractors that represent the two fate options. It has been debated whether cooperativity of molecular interactions is necessary to produce such multistability.Principal FindingsHere we take a general modeling approach and argue that this question is not relevant. We show that non-linearity can arise in two distinct models in which no explicit interaction between the two factors is assumed and that distinct chemical reaction kinetic formalisms can lead to the same (generic) dynamical system form. Moreover, we describe a novel type of bifurcation that produces a degenerate steady state that can explain the metastable state of indeterminacy prior to cell fate decision-making and is consistent with biological observations.ConclusionThe general model presented here thus offers a novel principle for linking regulatory circuits with the state of indeterminacy characteristic of multipotent (stem) cells.
Highlights
Development of the diversity of cell types in the mammalian body involves pluri- and multipotent stem and progenitor cells making fate decisions that are typically binary in nature, thereby committing to either of two to distinct cell lineages [1,2,3]
Cell fate-determining transcription factors (TFs) that directly control the expression of these lineage-specific genes play a central role in coordinating entire gene expression programs, for instance, ensuring their mutual exclusivity, by engaging in specific gene regulatory circuits [6,7,8,9]
Given the lack of knowledge of higher-level interactions we assume essential independence of the two inputs, the auto-stimulation and the cross inhibition. With this approach we arrive at two main conclusions: (a) We show that even without explicit assumption of proteinprotein interactions and cooperativity a general dynamical form can be derived in which multi-stability exists. (b) We find that for some parameter values of the dynamical system that correspond to a symmetry between auto stimulation and inhibition the system can give rise to a degenerate steady-state that corresponds to the indeterminate precursor state
Summary
Development of the diversity of cell types in the mammalian body involves pluri- and multipotent stem and progenitor cells making fate decisions that are typically binary in nature, thereby committing to either of two to distinct cell lineages [1,2,3]. The gene regulatory circuit motif in which two opposing fate-determining transcription factors inhibit each other but activate themselves has been used in mathematical models of binary cell fate decisions in multipotent stem or progenitor cells This simple circuit can generate multistability and explains the symmetric ‘‘poised’’ precursor state in which both factors are present in the cell at equal amounts as well as the resolution of this indeterminate state as the cell commits to either cell fate characterized by an asymmetric expression pattern of the two factors. This establishes the two alternative stable attractors that represent the two fate options. It has been debated whether cooperativity of molecular interactions is necessary to produce such multistability
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