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

ABSTRACT: 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/EBPalpha-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.

SUBMITTER: Chickarmane V

PROVIDER: S-EPMC2613533 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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

Chickarmane Vijay V Enver Tariq T Peterson Carsten C

PLoS computational biology 20090123 1

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-myelo ...[more]

PMID: 19165316

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Project description:BACKGROUND/OBJECTIVES:A cascade of gene activations under the control of Notch signalling is required during T-cell specification, when T-cell precursors gradually lose the potential to undertake other fates and become fully committed to the T-cell lineage. We elucidate how the gene/protein dynamics for a core transcriptional module governs this important process by computational means. METHODS:We first assembled existing knowledge about transcription factors known to be important for T-cell specification to form a minimal core module consisting of TCF-1, GATA-3, BCL11B, and PU.1 aiming at dynamical modeling. Model architecture was based on published experimental measurements of the effects on each factor when each of the others is perturbed. While several studies provided gene expression measurements at different stages of T-cell development, pure time series are not available, thus precluding a straightforward study of the dynamical interactions among these genes. We therefore translate stage dependent data into time series. A feed-forward motif with multiple positive feed-backs can account for the observed delay between BCL11B versus TCF-1 and GATA-3 activation by Notch signalling. With a novel computational approach, all 32 possible interactions among Notch signalling, TCF-1, and GATA-3 are explored by translating combinatorial logic expressions into differential equations for BCL11B production rate. RESULTS:Our analysis reveals that only 3 of 32 possible configurations, where GATA-3 works as a dimer, are able to explain not only the time delay, but very importantly, also give rise to irreversibility. The winning models explain the data within the 95% confidence region and are consistent with regard to decay rates. CONCLUSIONS:This first generation model for early T-cell specification has relatively few players. Yet it explains the gradual transition into a committed state with no return. Encoding logics in a rate equation setting allows determination of binding properties beyond what is possible in a Boolean network.

Dataset Information

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

Publications

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

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