title: Hierarchical differentiation of myeloid progenitors is encoded in the transcription factor network.
abstract: Hematopoiesis is an ideal model system for stem cell biology with advanced experimental access. A systems view on the interactions of core transcription factors is important for understanding differentiation mechanisms and dynamics. In this manuscript, we construct a Boolean network to model myeloid differentiation, specifically from common myeloid progenitors to megakaryocytes, erythrocytes, granulocytes and monocytes. By interpreting the hematopoietic literature and translating experimental evidence into Boolean rules, we implement binary dynamics on the resulting 11-factor regulatory network. Our network contains interesting functional modules and a concatenation of mutual antagonistic pairs. The state space of our model is a hierarchical, acyclic graph, typifying the principles of myeloid differentiation. We observe excellent agreement between the steady states of our model and microarray expression profiles of two different studies. Moreover, perturbations of the network topology correctly reproduce reported knockout phenotypes in silico. We predict previously uncharacterized regulatory interactions and alterations of the differentiation process, and line out reprogramming strategies.
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, München, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Krumsiek
authors.forename: Carsten
authors.initials: C
authors.lastname: Marr
authors.forename: Timm
authors.initials: T
authors.lastname: Schroeder
authors.forename: Fabian J
authors.initials: FJ
authors.lastname: Theis
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019295:Computational Biology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D053263:Gene Regulatory Networks / Q000235:genetics*; D051379:Mice; D008957:Models, Genetic; D023461:Myeloid Progenitor Cells / Q000166:cytology* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D049490:Systems Biology; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D014157:Transcription Factors