Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult zebrafish haematopoiesis

Tomasz Dobrzycki; Christopher B. Mahony; Monika Krecsmarik; Cansu Koyunlar; Rossella Rispoli; Joke Peulen-Zink; Kirsten Gussinklo; Bakhta Fedlaoui; Emma de Pater; Roger Patient; Rui Monteiro

doi:10.1038/s42003-020-0798-3

Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult zebrafish haematopoiesis

Tomasz Dobrzycki, Christopher B. Mahony, Monika Krecsmarik, Cansu Koyunlar, Rossella Rispoli, Joke Peulen-Zink, Kirsten Gussinklo, Bakhta Fedlaoui, Emma de Pater, Roger Patient, Rui Monteiro

Cancer and Genomic Sciences

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Abstract

Gata2 is a key transcription factor required to generate Haematopoietic Stem and Progenitor Cells (HSPCs) from haemogenic endothelium (HE); misexpression of Gata2 leads to haematopoietic disorders. Here we deleted a conserved enhancer (i4 enhancer) driving pan-endothelial expression of the zebrafish gata2a and showed that Gata2a is required for HE programming by regulating expression of runx1 and of the second Gata2 orthologue, gata2b. By 5 days, homozygous gata2a ^Δi4/Δi4 larvae showed normal numbers of HSPCs, a recovery mediated by Notch signalling driving gata2b and runx1 expression in HE. However, gata2a ^Δi4/Δi4 adults showed oedema, susceptibility to infections and marrow hypo-cellularity, consistent with bone marrow failure found in GATA2 deficiency syndromes. Thus, gata2a expression driven by the i4 enhancer is required for correct HE programming in embryos and maintenance of steady-state haematopoietic stem cell output in the adult. These enhancer mutants will be useful in exploring further the pathophysiology of GATA2-related deficiencies in vivo.

Original language	English
Article number	71
Number of pages	14
Journal	Communications Biology
Volume	3
Issue number	1
DOIs	https://doi.org/10.1038/s42003-020-0798-3
Publication status	Published - 13 Feb 2020

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
Medicine (miscellaneous)

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The role of TGFÃŸ signalling in angiogenic and haemogenic endothelical cell programming
Monteiro, R.
British Heart Foundation
1/03/18 → 31/10/20
Project: Research

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abstract = "Gata2 is a key transcription factor required to generate Haematopoietic Stem and Progenitor Cells (HSPCs) from haemogenic endothelium (HE); misexpression of Gata2 leads to haematopoietic disorders. Here we deleted a conserved enhancer (i4 enhancer) driving pan-endothelial expression of the zebrafish gata2a and showed that Gata2a is required for HE programming by regulating expression of runx1 and of the second Gata2 orthologue, gata2b. By 5 days, homozygous gata2a Δi4/Δi4 larvae showed normal numbers of HSPCs, a recovery mediated by Notch signalling driving gata2b and runx1 expression in HE. However, gata2a Δi4/Δi4 adults showed oedema, susceptibility to infections and marrow hypo-cellularity, consistent with bone marrow failure found in GATA2 deficiency syndromes. Thus, gata2a expression driven by the i4 enhancer is required for correct HE programming in embryos and maintenance of steady-state haematopoietic stem cell output in the adult. These enhancer mutants will be useful in exploring further the pathophysiology of GATA2-related deficiencies in vivo. ",

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AU - Koyunlar, Cansu

AU - Rispoli, Rossella

AU - Peulen-Zink, Joke

AU - Gussinklo, Kirsten

AU - Fedlaoui, Bakhta

AU - de Pater, Emma

AU - Patient, Roger

AU - Monteiro, Rui

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Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult zebrafish haematopoiesis

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The role of TGFÃŸ signalling in angiogenic and haemogenic endothelical cell programming

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