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Transcription factor (TF) networks determine cell-type identity by establishing and maintaining lineage-specific expression profiles, yet reconstruction of mammalian regulatory network models has been hampered by a lack of comprehensive functional validation of regulatory interactions. Here, we report comprehensive ChIP-Seq, transgenic and reporter gene experimental data that have allowed us to construct an experimentally validated regulatory network model for haematopoietic stem/progenitor cells (HSPCs). Model simulation coupled with subsequent experimental validation using single cell expression profiling revealed potential mechanisms for cell state stabilisation, and also how a leukaemogenic TF fusion protein perturbs key HSPC regulators. The approach presented here should help to improve our understanding of both normal physiological and disease processes.

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chromosomes, computational biology, genes, mouse, regulatory network, single cell, stem cells, systems biology, Animals, Cell Line, Chromatin Immunoprecipitation, Computer Simulation, Gene Expression Profiling, Gene Regulatory Networks, Hematopoiesis, Hematopoietic Stem Cells, Mice, Models, Theoretical, Sequence Analysis, DNA, Transcription Factors