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| Status |
Public on Sep 01, 2016 |
| Title |
Binary cell fate decision as high-dimensional critical state transition |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
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.
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| Contributor(s) |
Mojtahedi M, Skupin A, Zhou J, Castaño IG, Leong-Quong R, Chang HH, Giuliani A, Huang S |
| Citation missing |
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| Submission date |
Jun 30, 2015 |
| Last update date |
Jul 19, 2017 |
| Contact name |
Mitra Mojtahedi |
| E-mail(s) |
m.mojtahedi@ucalgary.ca
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| Organization name |
University of Calgary
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| Street address |
2500 University Dr. NW
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| City |
Calgary |
| State/province |
AB |
| ZIP/Postal code |
T2N 1N4 |
| Country |
Canada |
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| Platforms (1) |
| GPL13912 |
Agilent-028005 SurePrint G3 Mouse GE 8x60K Microarray (Feature Number version) |
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| Samples (10)
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| Relations |
| BioProject |
PRJNA288570 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE70405_RAW.tar |
39.8 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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