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

TY - JOUR

T1 - GFI1 proteins orchestrate the emergence of haematopoietic stem cells through recruitment of LSD1

AU - Thambyrajah, Roshana

AU - Mazan, Milena

AU - Patel, Rahima

AU - Moignard, Victoria

AU - Stefanska, Monika

AU - Marinopoulou, Elli

AU - Li, Yaoyong

AU - Lancrin, Christophe

AU - Clapes, Thomas

AU - Möröy, Tarik

AU - Robin, Catherine

AU - Miller, Crispin

AU - Cowley, Shaun

AU - Göttgens, Berthold

AU - Kouskoff, Valerie

AU - Lacaud, Georges

PY - 2016/1

Y1 - 2016/1

N2 - 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.

AB - 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.

KW - Animals

KW - Aorta

KW - Cell Differentiation

KW - DNA-Binding Proteins

KW - Embryo, Mammalian

KW - Hemangioblasts

KW - Hematopoietic Stem Cells

KW - Histone Demethylases

KW - Mice

KW - Transcription Factors

U2 - 10.1038/ncb3276

DO - 10.1038/ncb3276

M3 - Article

C2 - 26619147

SN - 1465-7392

VL - 18

SP - 21

EP - 32

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 1

ER -