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An experimentally validated network of nine haematopoietic transcription factors reveals mechanisms of cell state stability.

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Schütte, Judith 
Wang, Huange 
Antoniou, Stella 
Jarratt, Andrew 
Wilson, Nicola K 


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.



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

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eLife Sciences Publications, Ltd
Cancer Research Uk (None)
Leukaemia & Lymphoma Research (12029)
Biotechnology and Biological Sciences Research Council (BB/I00050X/1)
Cancer Research UK (CRUK-A19405)
Wellcome Trust (097922/Z/11/Z)
Medical Research Council (MC_PC_12009)
Leukemia & Lymphoma Society (7001-12)
Medical Research Council (MR/M008975/1)
Medical Research Council (G0900951)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (097922/Z/11/B)
British Heart Foundation (None)
CCF (None)
Medical Research Council (G0900951/1)
Research in the authors’ laboratories was supported by Bloodwise, The Wellcome Trust, Cancer Research UK, the Biotechnology and Biological Sciences Research Council, the National Institute of Health Research, the Medical Research Council, the MRC Molecular Haematology Unit (Oxford) core award, a Weizmann-UK “Making Connections” grant (Oxford) and core support grants by the Wellcome Trust to the Cambridge Institute for Medical Research (100140) and Wellcome Trust–MRC Cambridge Stem Cell Institute (097922).