Dataset Information

A general model for binary cell fate decision gene circuits with degeneracy: indeterminacy and switch behavior in the absence of cooperativity.

ABSTRACT:

Background

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.

Principal findings

Here 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.

Conclusion

The general model presented here thus offers a novel principle for linking regulatory circuits with the state of indeterminacy characteristic of multipotent (stem) cells.

SUBMITTER: Andrecut M

PROVIDER: S-EPMC3098230 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A general model for binary cell fate decision gene circuits with degeneracy: indeterminacy and switch behavior in the absence of cooperativity.

Andrecut Mircea M Halley Julianne D JD Winkler David A DA Huang Sui S

PloS one 20110519 5

<h4>Background</h4>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 commit ...[more]

PMID: 21625586

Similar Datasets

Project description:During commitment of a multipotent stem or progenitor cell to a particular lineage, a large number of genes alter their expression in a coordinated manner orchestrated by the gene regulatory network (GRN). The constraints imposed by the GRN govern how cells move in the high-dimensional gene expression state space and can be understood as a dynamical system in which phenotypic cell states (cell types) are attractors that stabilize the cell-type characteristic gene expression pattern against molecular noise. Despite insights from various theoretical models, it remains elusive how multipotent cells, when committing to a specific lineage, exit their attractor and enter a new distinct attractor. Here we show, using single-cell resolution monitoring of transcript patterns by qPCR that commitment of multipotent blood progenitor cells to either the erythroid or the myeloid lineage is preceded by a destabilization of the progenitorsâ?? attractor state and a slowing-down of relaxation of cells from outlier states, indicating a critical state transition (â??tipping pointâ??). The high-dimensionality of the system (many genes) and availability of individual trajectories of a large ensemble of systems (many cells) affords a novel signature for critical transition which can be predicted from theory: Decrease of correlation between cells and concomitant increase of correlation between genes as the cell population approaches the tipping point. Consistent with a destabilizing bifurcation that simultaneously opens access to the erythroid and myeloid attractors, differentiation signal for either lineage caused some cells to commit to the â??wrongâ?? fate; moreover providing conflicting signals resulted in a delayed decision at the bifurcation point that however was ultimately resolved by commitment to one fate. These results suggest that the theoretical framework of â??early-warning signsâ?? and critical transitions can be applied to ensembles of high-dimensional systems, offering a formal tool for analyzing single-cell omics data beyond current descriptive computational pattern recognition. Mouse blood progenitor cells (EML cell line) was exposed to EPO, IL-3/GM-CSF or a mixture of both cytokines and gene expression change was measured in sorted subpopulations wrt Sca1 progenitor surface marker expression. In total, there was 4 conditions (including control), three time points (including d0) and 20 samples (10 samples in duplicates) were analyzed. Two independent experiments were performed for each condition. The untreated progenitor cell population was used as control.

Project description:During commitment of a multipotent stem or progenitor cell to a particular lineage, a large number of genes alter their expression in a coordinated manner orchestrated by the gene regulatory network (GRN). The constraints imposed by the GRN govern how cells move in the high-dimensional gene expression state space and can be understood as a dynamical system in which phenotypic cell states (cell types) are attractors that stabilize the cell-type characteristic gene expression pattern against molecular noise. Despite insights from various theoretical models, it remains elusive how multipotent cells, when committing to a specific lineage, exit their attractor and enter a new distinct attractor. Here we show, using single-cell resolution monitoring of transcript patterns by qPCR that commitment of multipotent blood progenitor cells to either the erythroid or the myeloid lineage is preceded by a destabilization of the progenitors’ attractor state and a slowing-down of relaxation of cells from outlier states, indicating a critical state transition (“tipping point”). The high-dimensionality of the system (many genes) and availability of individual trajectories of a large ensemble of systems (many cells) affords a novel signature for critical transition which can be predicted from theory: Decrease of correlation between cells and concomitant increase of correlation between genes as the cell population approaches the tipping point. Consistent with a destabilizing bifurcation that simultaneously opens access to the erythroid and myeloid attractors, differentiation signal for either lineage caused some cells to commit to the “wrong” fate; moreover providing conflicting signals resulted in a delayed decision at the bifurcation point that however was ultimately resolved by commitment to one fate. These results suggest that the theoretical framework of “early-warning signs” and critical transitions can be applied to ensembles of high-dimensional systems, offering a formal tool for analyzing single-cell omics data beyond current descriptive computational pattern recognition.

Dataset Information

A general model for binary cell fate decision gene circuits with degeneracy: indeterminacy and switch behavior in the absence of cooperativity.

Background

Principal findings

Conclusion

Publications

A general model for binary cell fate decision gene circuits with degeneracy: indeterminacy and switch behavior in the absence of cooperativity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets