An experimentally validated network of nine haematopoietic transcription factors reveals mechanisms of cell state stability.
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Abstract
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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2050-084X
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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)