An experimentally validated network of nine haematopoietic transcription factors reveals mechanisms of cell state stability
Judith Schütte,
Huange Wang,
Stella Antoniou,
Andrew Jarratt,
Nicola K Wilson,
Joey Riepsaame,
Fernando J Calero-Nieto,
Victoria Moignard,
Silvia Basilico,
Sarah J Kinston,
Rebecca L Hannah,
Mun Chiang Chan,
Sylvia T Nürnberg,
Willem H Ouwehand,
Nicola Bonzanni,
Marella FTR de Bruijn,
Berthold Göttgens
Affiliations
Judith Schütte
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
Huange Wang
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
Stella Antoniou
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
Andrew Jarratt
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
Nicola K Wilson
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
Joey Riepsaame
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
Fernando J Calero-Nieto
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
Victoria Moignard
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
Silvia Basilico
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
Sarah J Kinston
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
Rebecca L Hannah
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
Mun Chiang Chan
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
Sylvia T Nürnberg
Department of Haematology, University of Cambridge, Cambridge, United Kingdom; NHS Blood and Transplant, Cambridge, United Kingdom
Willem H Ouwehand
Department of Haematology, University of Cambridge, Cambridge, United Kingdom; NHS Blood and Transplant, Cambridge, United Kingdom
Nicola Bonzanni
IBIVU Centre for Integrative Bioinformatics, VU University Amsterdam, Amsterdam, Netherlands; Netherlands Cancer Institute, Amsterdam, Netherlands
Marella FTR de Bruijn
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
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.
