Towards an understanding of lineage specification in hematopoietic stem cells: A mathematical model for the interaction of transcription factors GATA-1 and PU.1

摘要

In addition to their self-renewal capabilities, hematopoietic stem cellsguarantee the continuous supply of fully differentiated, functional cells ofvarious types in the peripheral blood. The process which controlsdifferentiation into the different lineages of the hematopoietic system(erythroid, myeloid, lymphoid) is referred to as lineage specification. Itrequires a potentially multi-step decision sequence which determines the fateof the cells and their successors. It is generally accepted that lineagespecification is regulated by a complex system of interacting transcriptionfactors. However, the underlying principles controlling this regulation arecurrently unknown. Here, we propose a simple quantitative model describing the interaction oftwo transcription factors. This model is motivated by experimental observationson the transcription factors GATA-1 and PU.1, both known to act as keyregulators and potential antagonists in the erythroid vs. myeloiddifferentiation processes of hematopoietic progenitor cells. We demonstrate theability of the model to account for the observed switching behavior of atransition from a state of low expression of both factors (undifferentiatedstate) to the dominance of one factor (differentiated state). Depending on theparameter choice, the model predicts two different possibilities to explain theexperimentally suggested, stem cell characterizing priming state of low levelco-expression. Whereas increasing transcription rates are sufficient to inducedifferentiation in one scenario, an additional system perturbation (bystochastic fluctuations or directed impulses) of transcription factor levels isrequired in the other case.