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, –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.
Highlights
Stem cell fates are decided upon the basis of which genes are turned ON/OFF
We develop a computational model to illustrate these principles as applied to the hematopoietic erythroid-myeloid lineage choice, where two master regulator genes, PU.1 and GATA1, function as a genetic switch
The GATA-1–PU.1 heterodimer inhibits GATA-1 transcription due to two factors: (i) PU.1 recruits the corepressor Rb and other chromatin modifying transcription factors and (ii) PU.1 prevents acetylation of GATA-1 by CBP, the latter which is required for erythroid differentiation
Summary
Prior to commitment, it has been observed that many genes are expressed at intermediate or basal levels for the hematopoietic stem cell system [1,2]. Such ‘‘priming’’ behavior for progenitors could allow for rapid deployment of transcription factors to implement particular genetic programs. A well studied subnetwork is that of PU. and GATA-1 It governs the erythroid - myeloid lineages and demonstrates both the commitment as well as priming features [6,7]. Recent investigations [14,15] focus on this mechanism to regulate choices of expressed genes as part of the macrophage/ neutrophil lineage
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