Abstract
BackgroundHematopoiesis is a highly orchestrated developmental process that comprises various developmental stages of the hematopoietic stem cells (HSCs). During development, the decision to leave the self-renewing state and selection of a differentiation pathway is regulated by a number of transcription factors. Among them, genes GATA-1 and PU.1 form a core negative feedback module to regulate the genetic switching between the cell fate choices of HSCs. Although extensive experimental studies have revealed the mechanisms to regulate the expression of these two genes, it is still unclear how this simple module regulates the genetic switching.MethodsIn this work we proposed a mathematical model to study the mechanisms of the GATA-PU.1 gene network in the determination of HSC differentiation pathways. We incorporated the mechanisms of GATA switch into the module, and developed a mathematical model that comprises three genes GATA-1, GATA-2 and PU.1. In addition, a novel multiple-objective optimization method was designed to infer unknown parameters in the proposed model by realizing different experimental observations. A stochastic model was also designed to describe the critical function of noise, due to the small copy numbers of molecular species, in determining the differentiation pathways.ResultsThe proposed deterministic model has successfully realized three stable steady states representing the priming and different progenitor cells as well as genetic switching between the genetic states under various experimental conditions. Using different values of GATA-1 synthesis rate for the GATA-1 protein availability in the chromatin sites during the time period of GATA switch, stochastic simulations for the first time have realized different proportions of cells leading to different developmental pathways under various experimental conditions.ConclusionsMathematical models provide testable predictions regarding the mechanisms and conditions for realizing different differentiation pathways of hematopoietic stem cells. This work represents the first attempt at using a discrete stochastic model to realize the decision of HSC differentiation pathways showing a multimodal distribution.
Highlights
Hematopoiesis is a highly orchestrated developmental process that comprises various developmental stages of the hematopoietic stem cells (HSCs)
Mathematical model of GATA-PU.1 gene network In this work we propose a mathematical model for the GATA-PU.1 regulatory network including genes GATA-1, GATA-2 and PU.1 (Figure 1A)
In this work we proposed a mathematical model to study the mechanisms of the GATA-PU.1 gene network in the determination of HSC differentiation pathways
Summary
Hematopoiesis is a highly orchestrated developmental process that comprises various developmental stages of the hematopoietic stem cells (HSCs). Hematopoiesis is a highly orchestrated developmental process that comprises the proliferation, differentiation and maturation of a very small population of self-renewing, pluripotent hematopoietic stem cells (HSC) for producing different types of blood cells, including erythrocyte, megakaryocyte, granulocyte, and macrophage [1,2]. During established that both PU. and GATA-1 ’autoregulate’ themselves, i.e. they stimulate their own production, as well as they are mutually antagonistic, i.e. they repress the production of each other [7,8,9]. The full understanding of the PU. and GATA-1 interaction is important for studying of the differentiation process of HSCs, which may be very useful in the clinical application of “differentiation therapy” for re-establishing the correct expression of PU. and/or GATA-1 within immature leukemic cells [12]
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