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bioRxiv · 10.1101/2022.03.24.485642

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

Koyunlar, C.·Gioacchino, E.·Vadgama, D.·de Looper, H.·Zink, J.·Hoogenboezem, R.·Havermans, M.·Bindels, E.·Dzierzak, E.·Touw, I. P.·de Pater, E.
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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. HighlightsO_LIMaturation of embryonic Gata2+/- HSPCs is disturbed due to aberrant endothelial gene expression and incomplete activation of hematopoietic transcriptional programming. C_LIO_LIGata2 activates Gfi1b to repress endothelial identity of embryonic HSPCs during maturation. C_LIO_LIHematopoietic-specific induction of gfi1b restores the number of embryonic HSCs in gata2b-/- zebrafish. C_LI

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Koyunlar, C., Gioacchino, E., Vadgama, D., de Looper, H., Zink, J., Hoogenboezem, R., Havermans, M., Bindels, E., Dzierzak, E., Touw, I. P., de Pater, E.. 2022-03-27. Gata2-regulated Gfi1b expression controls endothelial programming during endothelial-to-hematopoietic transition. https://doi.org/10.1101/2022.03.24.485642

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