hierarchical differentiation of myeloid progenitors is encoded in the transcription factor network等级分化的骨髓祖细胞转录因子网络编码.pdfVIP

Hierarchical Differentiation of Myeloid Progenitors Is Encoded in the Transcription Factor Network 1. 1. 2 1,3 Jan Krumsiek , Carsten Marr , Timm Schroeder , Fabian J. Theis * ¨ ¨ ¨ 1 Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum Munchen, Munchen, Germany, 2 Institute of Stem Cell Research, Helmholtz Zentrum Munchen, ¨ ¨ ¨ ¨ Munchen, Germany, 3 Department of Mathematics, Technische Universitat Munchen, Munchen, Germany 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 kno