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dc.contributor.authorThambyrajah, Roshanaen
dc.contributor.authorMazan, Milenaen
dc.contributor.authorPatel, Rahimaen
dc.contributor.authorMoignard, Victoriaen
dc.contributor.authorStefanska, Monikaen
dc.contributor.authorMarinopoulou, Ellien
dc.contributor.authorLi, Yaoyongen
dc.contributor.authorLancrin, Christopheen
dc.contributor.authorClapes, Thomasen
dc.contributor.authorMöröy, Tariken
dc.contributor.authorRobin, Catherineen
dc.contributor.authorMiller, Crispinen
dc.contributor.authorCowley, Shaunen
dc.contributor.authorGottgens, Bertholden
dc.contributor.authorKouskoff, Valerieen
dc.contributor.authorLacaud, Georgesen
dc.date.accessioned2015-10-28T12:39:50Z
dc.date.available2015-10-28T12:39:50Z
dc.date.issued2015-11-30en
dc.identifier.citationNature Cell Biology 2015, 18: 21–32. doi:10.1038/ncb3276en
dc.identifier.issn1465-7392
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/252433
dc.description.abstractIn 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-tohaematopoietic transition (EHT). Here, we establish the absolute requirement of the transcriptional repressors Growth Factor Independence 1 and 1B (GFI1 and GFI1B) 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.
dc.description.sponsorshipWe thank the staff at the Advanced Imaging, animal facility, Molecular Biology Core facilities and Flow Cytometry of CRUK Manchester Institute for technical support and Michael Lie-A-Ling and Elli Marinopoulou for initiating the DamID-PIP bioinformatics project. We thank members of the Stem Cell Biology group, the Stem Cell Haematopoiesis groups and Martin Gering for valuable advice and critical reading of the manuscript. Work in our laboratory is supported by the Leukaemia and Lymphoma Research Foundation (LLR), Cancer Research UK (CRUK) and the Biotechnology and Biological Sciences Research Council (BBSRC). SC is the recipient of an MRC senior fellowship (MR/J009202/1).
dc.languageEnglishen
dc.language.isoenen
dc.publisherNPG
dc.titleGFI1 proteins orchestrate the emergence of Haematopoietic Stem Cells through recruitment of LSD1en
dc.title.alternativeGFI1 proteins regulate stem cell formation in the AGMen
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ncb3276en
prism.endingPage32
prism.publicationDate2015en
prism.publicationNameNature Cell Biologyen
prism.startingPage21
prism.volume18en
dc.rioxxterms.funderMRC
dc.rioxxterms.funderCRUK
dc.rioxxterms.funderBBSRC
dc.rioxxterms.projectidMR/J009202/1
dcterms.dateAccepted2015-10-26en
rioxxterms.versionofrecord10.1038/ncb3276en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-11-30en
dc.contributor.orcidMoignard, Victoria [0000-0001-5089-5875]
dc.contributor.orcidGottgens, Berthold [0000-0001-6302-5705]
dc.identifier.eissn1476-4679
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idLeukaemia & Lymphoma Research (12029)
pubs.funder-project-idWellcome Trust (097922/Z/11/Z)
pubs.funder-project-idMRC (MC_PC_12009)
pubs.funder-project-idLeukemia & Lymphoma Society (7001-12)
pubs.funder-project-idCancer Research UK (12765)
pubs.funder-project-idBBSRC (BB/I00050X/1)
rioxxterms.freetoread.startdate2016-05-30


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