title: An experimentally validated network of nine haematopoietic transcription factors reveals mechanisms of cell state stability.
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.
authors.affiliation: 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.
authors.forename: Judith
authors.initials: J
authors.lastname: Schütte
authors.affiliation: 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.
authors.forename: Huange
authors.initials: H
authors.lastname: Wang
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Stella
authors.initials: S
authors.lastname: Antoniou
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Jarratt
authors.affiliation: 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.
authors.forename: Nicola K
authors.initials: NK
authors.lastname: Wilson
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Joey
authors.initials: J
authors.lastname: Riepsaame
authors.affiliation: 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.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Calero-Nieto
authors.affiliation: 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.
authors.forename: Victoria
authors.initials: V
authors.lastname: Moignard
authors.affiliation: 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.
authors.forename: Silvia
authors.initials: S
authors.lastname: Basilico
authors.affiliation: 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.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Kinston
authors.affiliation: 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.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Hannah
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Mun Chiang
authors.initials: MC
authors.lastname: Chan
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|NHS Blood and Transplant, Cambridge, United Kingdom.
authors.forename: Sylvia T
authors.initials: ST
authors.lastname: Nürnberg
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|NHS Blood and Transplant, Cambridge, United Kingdom.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: IBIVU Centre for Integrative Bioinformatics, VU University Amsterdam, Amsterdam, Netherlands.|Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Nicola
authors.initials: N
authors.lastname: Bonzanni
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Marella Ftr
authors.initials: MF
authors.lastname: de Bruijn
authors.affiliation: 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.
authors.forename: Berthold
authors.identifier: http://orcid.org/0000-0001-6302-5705
authors.initials: B
authors.lastname: Göttgens
mesh_terms: D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D003198:Computer Simulation; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D051379:Mice; D008962:Models, Theoretical; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014157:Transcription Factors
keywords: chromosomes; computational biology; genes; mouse; regulatory network; single cell; stem cells; systems biology