Vijay Chickarmane, Tariq Enver and Carsten Peterson
Computational modeling of the hematopoietic erythroid-myeloid switch reveals insights into co-operativity, priming and irreversibility
PLoS Computational Biology 5, e1000268 (2009)
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 co-factor which is regulated as well as recruited by one of the master genes to bind to the antagonistic partner, which is necessary for bistability and hence switch-like behavior. An interesting fallout from this architecture is that suppression of the co-factor 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/EBP$\alpha$--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.
LU TP 08-13
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 co-factor which is regulated as well as recruited by one of the master genes to bind to the antagonistic partner, which is necessary for bistability and hence switch-like behavior. An interesting fallout from this architecture is that suppression of the co-factor 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/EBP$\alpha$--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.
LU TP 08-13