GFI1 proteins orchestrate the emergence of haematopoietic stem cells through recruitment of LSD1

Roshana Thambyrajah, Milena Mazan, Rahima Patel, Victoria Moignard, Monika Stefanska, Elli Marinopoulou, Yaoyong Li, Christophe Lancrin, Thomas Clapes, Tarik Möröy, Catherine Robin, Crispin Miller, Shaun Cowley, Berthold Göttgens, Valerie Kouskoff, Georges Lacaud

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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.

Original languageEnglish
Pages (from-to)21-32
Number of pages12
JournalNature Cell Biology
Volume18
Issue number1
DOIs
Publication statusPublished - Jan 2016

Keywords

  • Animals
  • Aorta
  • Cell Differentiation
  • DNA-Binding Proteins
  • Embryo, Mammalian
  • Hemangioblasts
  • Hematopoietic Stem Cells
  • Histone Demethylases
  • Mice
  • Transcription Factors

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    Thambyrajah, R., Mazan, M., Patel, R., Moignard, V., Stefanska, M., Marinopoulou, E., Li, Y., Lancrin, C., Clapes, T., Möröy, T., Robin, C., Miller, C., Cowley, S., Göttgens, B., Kouskoff, V., & Lacaud, G. (2016). GFI1 proteins orchestrate the emergence of haematopoietic stem cells through recruitment of LSD1. Nature Cell Biology, 18(1), 21-32. https://doi.org/10.1038/ncb3276