title: Repression of arterial genes in hemogenic endothelium is sufficient for haematopoietic fate acquisition.
abstract: Changes in cell fate and identity are essential for endothelial-to-haematopoietic transition (EHT), an embryonic process that generates the first adult populations of haematopoietic stem cells (HSCs) from hemogenic endothelial cells. Dissecting EHT regulation is a critical step towards the production of in vitro derived HSCs. Yet, we do not know how distinct endothelial and haematopoietic fates are parsed during the transition. Here we show that genes required for arterial identity function later to repress haematopoietic fate. Tissue-specific, temporally controlled, genetic loss of arterial genes (Sox17 and Notch1) during EHT results in increased production of haematopoietic cells due to loss of Sox17-mediated repression of haematopoietic transcription factors (Runx1 and Gata2). However, the increase in EHT can be abrogated by increased Notch signalling. These findings demonstrate that the endothelial haematopoietic fate switch is actively repressed in a population of endothelial cells, and that derepression of these programs augments haematopoietic output.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Carlos O
authors.initials: CO
authors.lastname: Lizama
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Hawkins
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Schmitt
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Frank L
authors.initials: FL
authors.lastname: Bos
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Joan P
authors.initials: JP
authors.lastname: Zape
authors.affiliation: Department of Nutrition, Diabetes, and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Cautivo
authors.affiliation: Burke Medical Research Institute, White Plains, New York 10605, USA.|Department of Neuroscience, Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10065, USA.|Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Hugo
authors.initials: H
authors.lastname: Borges Pinto
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.|Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Rhyner
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.affiliation: Burke Medical Research Institute, White Plains, New York 10605, USA.|Department of Neuroscience, Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10065, USA.|Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Donohoe
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.|Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Wythe
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94158, USA.|Department of Pediatrics, Division of Neonatology, School of Medicine, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Zovein
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000196:embryology*; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D005260:Female; D050989:GATA2 Transcription Factor / Q000378:metabolism*; D017930:Genes, Reporter; D024002:HMGB Proteins / Q000502:physiology*; D055018:Hemangioblasts / Q000502:physiology*; D006410:Hematopoiesis; D051379:Mice; D011247:Pregnancy; D051881:Receptor, Notch1 / Q000378:metabolism; D055760:SOXF Transcription Factors / Q000502:physiology*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D024002:HMGB Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C493726:Runx1 protein, mouse; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse