Gata2-regulated Gfi1b expression controls endothelial programming during endothelial-to-hematopoietic transition

Cansu Koyunlar, Emanuele Gioacchino, Disha Vadgama, Hans W J de Looper, Joke Zink, Mariette Ter Borg, Remco Hoogenboezem, Marije Havermans, Mathijs Arnoud Sanders, Eric Bindels, Elaine A Dzierzak, Ivo P Touw, Emma de Pater*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)

Abstract

The first hematopoietic stem cells (HSCs) are formed through endothelial-to-hematopoietic transition (EHT) events during embryonic development. The transcription factor GATA2 is a crucial regulator of EHT and HSC function throughout life. Because GATA2 haploinsufficiency patients have inborn mutations, prenatal defects are likely to have an influence on disease development. In mice, Gata2 haploinsufficiency (Gata2+/-) reduces the number and the functionality of embryonic hematopoietic stem and progenitor cells (HSPCs) generated through EHT. However, the embryonic HSPC pool is heterogeneous and the mechanisms underlying this defect in Gata2+/- embryos are unclear. Here, we investigated whether Gata2 haploinsufficiency selectively affects a cellular subset undergoing EHT. We show that Gata2+/- HSPCs initiate but cannot fully activate hematopoietic programming during EHT. In addition, due to reduced activity of the endothelial repressor Gfi1b, Gata2+/- HSPCs cannot repress the endothelial identity to complete maturation. Finally, we show that hematopoietic-specific induction of gfi1b can restore HSC production in gata2b-null (gata2b-/-) zebrafish embryos. This study illustrates pivotal roles of Gata2 on the regulation of transcriptional network governing HSPC identity throughout EHT.

Original languageEnglish
Pages (from-to)2082-2093
Number of pages12
JournalBlood advances
Volume7
Issue number10
Early online date17 Jan 2023
DOIs
Publication statusPublished - 23 May 2023

Bibliographical note

Funding Information:
The authors thank the members of the de Pater laboratory for helpful discussions. The authors thank the Experimental Animal Facility of the Erasmus Medical Center for animal husbandry and the Erasmus Optical Imaging Center for confocal microscopy services. This work is supported by the European Hematology Association (junior nonclinical research fellowship) (E.d.P.), the Dutch Cancer Foundation KWF/Alpe d’HuZes (SK10321) (E.d.P.), and the Daniel den Hoed Foundation for support of the Cancer Genome Editing Center (I.P.T.).

Funding Information:
This work is supported by the European Hematology Association (junior nonclinical research fellowship) (E.d.P.), the Dutch Cancer Foundation KWF/Alpe d’HuZes (SK10321) (E.d.P.), and the Daniel den Hoed Foundation for support of the Cancer Genome Editing Center (I.P.T.).

Publisher Copyright:
© 2023 by The American Society of Hematology.

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