Figure 4

Studying the biological program governing myeloid progenitor differentiation. (a) The differentiation of a common myeloid progenitor towards four different blood cell types is considered. (b) The network topology proposed by Krumsiek et al. (c) The set of experimental observations indicates that, starting from the progenitor cellular state (step 0), each state characterizing a different cell type is reached after 20 steps and the system stabilizes (indicated by a star). The megakaryocyte GATA-2 was observed as active in experiments but was inactive in the model from Krumsiek et al. (red box). (d) 15 of the possible interactions were identified as required (solid red and green arrows) and 2 were identified as disallowed (solid black arrows) in the cABN satisfying the constraints in c. (e) If all interactions from the original model in b are considered as definite, the correct expression of megakaryocyte GATA-2 can be achieved by including one of 12 possible interactions. (f) The experimental constraints are modified to specify that the cell-fate decision is made in response to whether the hypothetical signals X and Y are present or not. (g) Two minimal models are identified when considering the hypothetical signals. Three novel interactions (signal X activating Fli1, signal Y activating EKLF and Fli1 activating GATA-2) appear in both models. In the first minimal model Y represses Gfi1, while in the second this signal activates cjun.