title: The Hemogenic Competence of Endothelial Progenitors Is Restricted by Runx1 Silencing during Embryonic Development.
abstract: It is now well-established that hematopoietic stem cells (HSCs) and progenitor cells originate from a specialized subset of endothelium, termed hemogenic endothelium (HE), via an endothelial-to-hematopoietic transition. However, the molecular mechanisms determining which endothelial progenitors possess this hemogenic potential are currently unknown. Here, we investigated the changes in hemogenic potential in endothelial progenitors at the early stages of embryonic development. Using an ETV2::GFP reporter mouse to isolate emerging endothelial progenitors, we observed a dramatic decrease in hemogenic potential between embryonic day (E)7.5 and E8.5. At the molecular level, Runx1 is expressed at much lower levels in E8.5 intra-embryonic progenitors, while Bmi1 expression is increased. Remarkably, the ectopic expression of Runx1 in these progenitors fully restores their hemogenic potential, as does the suppression of BMI1 function. Altogether, our data demonstrate that hemogenic competency in recently specified endothelial progenitors is restrained through the active silencing of Runx1 expression.
authors.affiliation: Cancer Research UK Stem Cell Hematopoiesis Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Alexia
authors.initials: A
authors.lastname: Eliades
authors.affiliation: Cancer Research UK Stem Cell Hematopoiesis Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wareing
authors.affiliation: Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Elli
authors.initials: E
authors.lastname: Marinopoulou
authors.affiliation: Cancer Research UK Stem Cell Hematopoiesis Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Muhammad Z H
authors.initials: MZH
authors.lastname: Fadlullah
authors.affiliation: Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Rahima
authors.initials: R
authors.lastname: Patel
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, UK.
authors.forename: Joanna B
authors.initials: JB
authors.lastname: Grabarek
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, UK.
authors.forename: Berenika
authors.initials: B
authors.lastname: Plusa
authors.affiliation: Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK. Electronic address: georges.lacaud@cruk.manchester.ac.uk.
authors.forename: Georges
authors.initials: G
authors.lastname: Lacaud
authors.affiliation: Cancer Research UK Stem Cell Hematopoiesis Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK. Electronic address: valerie.kouskoff@cruk.manchester.ac.uk.
authors.forename: Valerie
authors.initials: V
authors.lastname: Kouskoff
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D066026:Endothelial Progenitor Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D049452:Green Fluorescent Proteins / Q000378:metabolism; D055018:Hemangioblasts / Q000166:cytology* / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics; D016130:Immunophenotyping; D008297:Male; D008813:Mice, Inbred ICR; D020411:Oligonucleotide Array Sequence Analysis; D063150:Polycomb Repressive Complex 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D059010:Single-Cell Analysis; D051785:Smad Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C489421:Bmi1 protein, mouse; D055415:Bone Morphogenetic Protein 4; D050676:Core Binding Factor Alpha 2 Subunit; C503994:ER71 protein, mouse; D011518:Proto-Oncogene Proteins; D051785:Smad Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D063150:Polycomb Repressive Complex 1