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Computational modeling of the hematopoietic erythroid-myeloid switch reveals insights into cooperativity, priming, and irreversibility

Chickarmane, Vijay and Enver, Tariq and Peterson, Carsten (2009) Computational modeling of the hematopoietic erythroid-myeloid switch reveals insights into cooperativity, priming, and irreversibility. PLoS Computational Biology, 5 (1). Art. No. e1000268. ISSN 1553-734X. PMCID PMC2613533.

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Hematopoietic stem cell lineage choices are decided by genetic networks that are turned ON/OFF in a switch-like manner. However, prior to lineage commitment, genes are primed at low expression levels. Understanding the underlying molecular circuitry in terms of how it governs both a primed state and, at the other extreme, a committed state is of relevance not only to hematopoiesis but also to developmental systems in general. We develop a computational model for the hematopoietic erythroid-myeloid lineage decision, which is determined by a genetic switch involving the genes PU.1 and GATA-1. Dynamical models based upon known interactions between these master genes, such as mutual antagonism and autoregulation, fail to make the system bistable, a desired feature for robust lineage determination. We therefore suggest a new mechanism involving a cofactor that is regulated as well as recruited by one of the master genes to bind to the antagonistic partner that is necessary for bistability and hence switch-like behavior. An interesting fallout from this architecture is that suppression of the cofactor through external means can lead to a loss of cooperativity, and hence to a primed state for PU.1 and GATA-1. The PU.1–GATA-1 switch also interacts with another mutually antagonistic pair, C/EBPα–FOG-1. The latter pair inherits the state of its upstream master genes and further reinforces the decision due to several feedback loops, thereby leading to irreversible commitment. The genetic switch, which handles the erythroid-myeloid lineage decision, is an example of a network that implements both a primed and a committed state by regulating cooperativity through recruitment of cofactors. Perturbing the feedback between the master regulators and downstream targets suggests potential reprogramming strategies. The approach points to a framework for lineage commitment studies in general and could aid the search for lineage-determining genes.

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Additional Information:© 2009 PubMed Central. Received: June 16, 2008; Accepted: December 5, 2008; Published: January 23, 2009. This research was in part supported by the Swedish Foundation for Strategic Research through a Senior Individual Grant, the National Science Foundation FIBR Award EF-0330786, the UK Medical Research Council, the Leukemia Research Fund UK, and the EU EuroSyStem and Estools projects. The authors have declared that no competing interests exist. Conceived and designed the experiments: VC CP. Performed the experiments: VC CP. Analyzed the data: VC TE CP. Contributed reagents/materials/analysis tools: VC. Wrote the paper: VC TE CP. Contributed with stem cell biology knowledge: TE.
Funding AgencyGrant Number
Swedish Foundation for Strategic ResearchUNSPECIFIED
Medical Research Council (UK)UNSPECIFIED
Leukemia Research Fund UKUNSPECIFIED
EU EuroSyStem and Estools projectsUNSPECIFIED
Issue or Number:1
PubMed Central ID:PMC2613533
Record Number:CaltechAUTHORS:20090427-132213157
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Official Citation:Chickarmane V, Enver T, Peterson C (2009) Computational Modeling of the Hematopoietic Erythroid-Myeloid Switch Reveals Insights into Cooperativity, Priming, and Irreversibility. PLoS Comput Biol 5(1): e1000268. doi:10.1371/journal.pcbi.1000268
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14088
Deposited By: Jason Perez
Deposited On:10 Aug 2009 18:34
Last Modified:12 Feb 2020 21:31

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