  In addition to their self-renewal capabilities, hematopoietic stem cells
guarantee the continuous supply of fully differentiated, functional cells of
various types in the peripheral blood. The process which controls
differentiation into the different lineages of the hematopoietic system
(erythroid, myeloid, lymphoid) is referred to as lineage specification. It
requires a potentially multi-step decision sequence which determines the fate
of the cells and their successors. It is generally accepted that lineage
specification is regulated by a complex system of interacting transcription
factors. However, the underlying principles controlling this regulation are
currently unknown.
  Here, we propose a simple quantitative model describing the interaction of
two transcription factors. This model is motivated by experimental observations
on the transcription factors GATA-1 and PU.1, both known to act as key
regulators and potential antagonists in the erythroid vs. myeloid
differentiation processes of hematopoietic progenitor cells. We demonstrate the
ability of the model to account for the observed switching behavior of a
transition from a state of low expression of both factors (undifferentiated
state) to the dominance of one factor (differentiated state). Depending on the
parameter choice, the model predicts two different possibilities to explain the
experimentally suggested, stem cell characterizing priming state of low level
co-expression. Whereas increasing transcription rates are sufficient to induce
differentiation in one scenario, an additional system perturbation (by
stochastic fluctuations or directed impulses) of transcription factor levels is
required in the other case.
