ArticlePloS one2011
A general model for binary cell fate decision gene circuits with degeneracy: indeterminacy and switch behavior in the absence of cooperativity.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed.
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- A computational model of stem cell molecular mechanism to maintain tissue homeostasis.PloS one · 2020Article
- Intracellular Energy Variability Modulates Cellular Decision-Making Capacity.Scientific reports · 2019Article
- Variable cellular decision-making behavior in a constant synthetic network topology.BMC bioinformatics · 2019Article
- CD4Frontiers in immunology · 2018Article
- Inhibitors Alter the Stochasticity of Regulatory Proteins to Force Cells to Switch to the Other State in the Bistable System.Scientific reports · 2017Article
- Nanog Fluctuations in Embryonic Stem Cells Highlight the Problem of Measurement in Cell Biology.Biophysical journal · 2017Article
- BTR: training asynchronous Boolean models using single-cell expression data.BMC bioinformatics · 2016Article
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- Pluripotency, Differentiation, and Reprogramming: A Gene Expression Dynamics Model with Epigenetic Feedback Regulation.PLoS computational biology · 2015Article
- Increased robustness of early embryogenesis through collective decision-making by key transcription factors.BMC systems biology · 2015Article
- Boolean network model for GPR142 against Type 2 diabetes and relative dynamic change ratio analysis using systems and biological circuits approach.Systems and synthetic biology · 2015Article
- Reshaping the epigenetic landscape during early flower development: induction of attractor transitions by relative differences in gene decay rates.BMC systems biology · 2015Article
- Bifurcation dynamics and determination of alternate cell fates in bipotent progenitor cells.Cognitive neurodynamics · 2015Article
- Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis.Frontiers in oncology · 2015Review
- The AhR agonist VAF347 augments retinoic acid-induced differentiation in leukemia cells.FEBS open bio · 2015Article
- Towards elucidating the connection between epithelial-mesenchymal transitions and stemness.Journal of the Royal Society, Interface · 2014Article
- The three-way switch operation of Rac1/RhoA GTPase-based circuit controlling amoeboid-hybrid-mesenchymal transition.Scientific reports · 2014Article
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4 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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