Mathematical modeling of simple transcription factor networks
The hematopoietic system consists of a variety of functionally different cell types. Whereas mature cell types have specific but limited life spans, the population of hematopoietic stem cells (HSC) is considered to exist throughout the whole life of the organism. This ability of maintaining its own population (self-renewal property) is one important constituent of the definition of HSC. However, HSC have, furthermore, to ensure the supply of functionally differentiated cells meeting the actual needs of the organism. The process which controls the development of undifferentiated HSC into one specific functional developmental direction (i.e. one specific hematopoietic lineage) is called lineage specification. Although it is speculated that this process is governed by the interplay of several different transcription factors (TF), the underlying general principles are currently unknown. In this work, a simple mathematical model (using an ordinary differential equation as well as a stochastic single molecule based approach), describing the interaction of two TF (GATA-1, PU.1), is proposed. Both TF are known to be involved in the process of erythroid/myeloid differentiation of HSC. The described model structure is based on principles suggested for the description of general genetic switches. However, it is involving specific knowledge on the biochemical structure of GATA-1 and PU.1, particularly experimentally observed mechanisms of mutual inhibition. The model analysis is suggesting that there are two possible scenarios for the negative feedback effect of PU.1 on the transcription of GATA-1 which are sufficient to induce a genetic switch behavior. Both are assuming the formation of a GATA-1/PU.1 complex. Whereas in scenario 1 this complex is acting as a transcription repressor by blocking GATA-1 mRNA production, in scenario 2 it is blocking the GATA-1 binding to its promoter (as proposed experimentally). The latter mechanism, however, does only generate a switch-like behavior if one is assuming a certain decay of the GATA-1/PU.1 complex.
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