title: GFI1 proteins orchestrate the emergence of haematopoietic stem cells through recruitment of LSD1.
abstract: In vertebrates, the first haematopoietic stem cells (HSCs) with multi-lineage and long-term repopulating potential arise in the AGM (aorta-gonad-mesonephros) region. These HSCs are generated from a rare and transient subset of endothelial cells, called haemogenic endothelium (HE), through an endothelial-to-haematopoietic transition (EHT). Here, we establish the absolute requirement of the transcriptional repressors GFI1 and GFI1B (growth factor independence 1 and 1B) in this unique trans-differentiation process. We first demonstrate that Gfi1 expression specifically defines the rare population of HE that generates emerging HSCs. We further establish that in the absence of GFI1 proteins, HSCs and haematopoietic progenitor cells are not produced in the AGM, revealing the critical requirement for GFI1 proteins in intra-embryonic EHT. Finally, we demonstrate that GFI1 proteins recruit the chromatin-modifying protein LSD1, a member of the CoREST repressive complex, to epigenetically silence the endothelial program in HE and allow the emergence of blood cells.
authors.affiliation: CRUK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Roshana
authors.initials: R
authors.lastname: Thambyrajah
authors.affiliation: CRUK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.|Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Milena
authors.initials: M
authors.lastname: Mazan
authors.affiliation: CRUK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Rahima
authors.initials: R
authors.lastname: Patel
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research &Wellcome Trust and MRC Stem Cell Institute, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Victoria
authors.identifier: http://orcid.org/0000-0001-5089-5875
authors.initials: V
authors.lastname: Moignard
authors.affiliation: CRUK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Monika
authors.initials: M
authors.lastname: Stefanska
authors.affiliation: CRUK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Elli
authors.initials: E
authors.lastname: Marinopoulou
authors.affiliation: CRUK Computational Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Yaoyong
authors.initials: Y
authors.lastname: Li
authors.affiliation: CRUK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.|European Molecular Biology Laboratory, Mouse Biology Unit, 00015 Monterotondo, Italy.
authors.forename: Christophe
authors.identifier: http://orcid.org/0000-0003-0028-7374
authors.initials: C
authors.lastname: Lancrin
authors.affiliation: Hubrecht Institute, Uppsalalaan 8, 3584 CT Utrecht, Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Clapes
authors.affiliation: Institut de recherches cliniques de Montréal (IRCM) and département de microbiologie et immunologie, Université de Montréal, Montréal, Quebec H2W 1R7, Canada.
authors.forename: Tarik
authors.initials: T
authors.lastname: Möröy
authors.affiliation: Hubrecht Institute, Uppsalalaan 8, 3584 CT Utrecht, Netherlands.
authors.forename: Catherine
authors.initials: C
authors.lastname: Robin
authors.affiliation: CRUK Computational Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Crispin
authors.initials: C
authors.lastname: Miller
authors.affiliation: Department of Biochemistry, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Shaun
authors.initials: S
authors.lastname: Cowley
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research &Wellcome Trust and MRC Stem Cell Institute, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Berthold
authors.identifier: http://orcid.org/0000-0001-6302-5705
authors.initials: B
authors.lastname: Göttgens
authors.affiliation: CRUK Stem Cell Haematopoiesis Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Valerie
authors.initials: V
authors.lastname: Kouskoff
authors.affiliation: CRUK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Georges
authors.identifier: http://orcid.org/0000-0002-5630-2417
authors.initials: G
authors.lastname: Lacaud
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000196:embryology; D002454:Cell Differentiation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D055018:Hemangioblasts / Q000166:cytology / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D056466:Histone Demethylases / Q000378:metabolism*; D051379:Mice; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; D014157:Transcription Factors; D056466:Histone Demethylases; C504076:KDM1a protein, mouse