Essential role for Gata2 in modulating lineage output from hematopoietic stem cells in zebrafish

Emanuele Gioacchino; Cansu Koyunlar; Joke Zink; Hans de Looper; Madelon de Jong; Tomasz Dobrzycki; Christopher B. Mahony; Remco Hoogenboezem; Dennis Bosch; Paulina M.H. van Strien; Martin E. van Royen; Pim J. French; Eric Bindels; Kirsten J. Gussinklo; Rui Monteiro; Ivo P. Touw; Emma de Pater

doi:10.1182/bloodadvances.2020002993

Essential role for Gata2 in modulating lineage output from hematopoietic stem cells in zebrafish

Emanuele Gioacchino, Cansu Koyunlar, Joke Zink, Hans de Looper, Madelon de Jong, Tomasz Dobrzycki, Christopher B. Mahony, Remco Hoogenboezem, Dennis Bosch, Paulina M.H. van Strien, Martin E. van Royen, Pim J. French, Eric Bindels, Kirsten J. Gussinklo, Rui Monteiro, Ivo P. Touw, Emma de Pater^*

^*Corresponding author for this work

Cancer and Genomic Sciences

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Abstract

The differentiation of hematopoietic stem cells (HSCs) is tightly controlled to ensure a proper balance between myeloid and lymphoid cell output. GATA2 is a pivotal hematopoietic transcription factor required for generation and maintenance of HSCs. GATA2 is expressed throughout development, but because of early embryonic lethality in mice, its role during adult hematopoiesis is incompletely understood. Zebrafish contains 2 orthologs of GATA2: Gata2a and Gata2b, which are expressed in different cell types. We show that the mammalian functions of GATA2 are split between these orthologs. Gata2bdeficient zebrafish have a reduction in embryonic definitive hematopoietic stem and progenitor cell (HSPC) numbers, but are viable. This allows us to uniquely study the role of GATA2 in adult hematopoiesis. gata2b mutants have impaired myeloid lineage differentiation. Interestingly, this defect arises not in granulocyte-monocyte progenitors, but in HSPCs. Gata2b-deficient HSPCs showed impaired progression of the myeloid transcriptional program, concomitant with increased coexpression of lymphoid genes. This resulted in a decrease in myeloid-programmed progenitors and a relative increase in lymphoid-programmed progenitors. This shift in the lineage output could function as an escape mechanism to avoid a block in lineage differentiation. Our study helps to deconstruct the functions of GATA2 during hematopoiesis and shows that lineage differentiation flows toward a lymphoid lineage in the absence of Gata2b.

Original language	English
Pages (from-to)	2687-2700
Number of pages	14
Journal	Blood Advances
Volume	5
Issue number	13
Early online date	26 Jun 2021
DOIs	https://doi.org/10.1182/bloodadvances.2020002993
Publication status	Published - 13 Jul 2021

Bibliographical note

Funding Information:
The authors thank members of the E.d.P., I.P.T., Raaijmakers, and Schneider-Kramann laboratories for helpful discussions; Tom Cupe-do (Erasmus MC) and Elaine Dzierzak (University of Edinburgh) for careful reading of the manuscript; and the Experimental Animal Facility of Erasmus MC for animal husbandry and the Erasmus Optical Imaging Center for confocal microscopy services. The visual abstract was created with BioRender.com. This research was supported by the European Hematology Association (junior nonclinical research fellowship) (E.d.P.), the Dutch Cancer Foundation/Alpe d’HuZes (SK10321) (E.d.P.), the British Heart Foundation (BHF IBSR fellowship FS/13/50/30436) (R.M. and C.B.M.), the Wellcome Trust (PhD scholarship #WT102345/Z/13/ Z) (T.D.), the Daniel den Hoed Foundation for support of the Cancer Genome Editing Center (I.P.T.), and the Josephine Nefkens Foundation for purchase of the Chromium (103 Genomics) (I.P.T.).

Publisher Copyright:
© 2021 by The American Society of Hematology.

ASJC Scopus subject areas

Hematology

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10.1182/bloodadvances.2020002993

GioacchinoE2021Essential
Emanuele Gioacchino, Cansu Koyunlar, Joke Zink, Hans de Looper, Madelon de Jong, Tomasz Dobrzycki, Christopher B. Mahony, Remco Hoogenboezem, Dennis Bosch, Paulina M. H. van Strien, Martin E. van Royen, Pim J. French, Eric Bindels, Kirsten J. Gussinklo, Rui Monteiro, Ivo P. Touw, Emma de Pater; Essential role for Gata2 in modulating lineage output from hematopoietic stem cells in zebrafish. Blood Adv 2021; 5 (13): 2687–2700. doi: https://doi.org/10.1182/bloodadvances.2020002993 © 2021 by The American Society of Hematology
Final published version, 29.6 MBLicence: None: All rights reserved

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Gioacchino, E., Koyunlar, C., Zink, J., de Looper, H., de Jong, M., Dobrzycki, T., Mahony, C. B., Hoogenboezem, R., Bosch, D., van Strien, P. M. H., van Royen, M. E., French, P. J., Bindels, E., Gussinklo, K. J., Monteiro, R., Touw, I. P., & de Pater, E. (2021). Essential role for Gata2 in modulating lineage output from hematopoietic stem cells in zebrafish. Blood Advances, 5(13), 2687-2700. Advance online publication. https://doi.org/10.1182/bloodadvances.2020002993

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title = "Essential role for Gata2 in modulating lineage output from hematopoietic stem cells in zebrafish",

abstract = "The differentiation of hematopoietic stem cells (HSCs) is tightly controlled to ensure a proper balance between myeloid and lymphoid cell output. GATA2 is a pivotal hematopoietic transcription factor required for generation and maintenance of HSCs. GATA2 is expressed throughout development, but because of early embryonic lethality in mice, its role during adult hematopoiesis is incompletely understood. Zebrafish contains 2 orthologs of GATA2: Gata2a and Gata2b, which are expressed in different cell types. We show that the mammalian functions of GATA2 are split between these orthologs. Gata2bdeficient zebrafish have a reduction in embryonic definitive hematopoietic stem and progenitor cell (HSPC) numbers, but are viable. This allows us to uniquely study the role of GATA2 in adult hematopoiesis. gata2b mutants have impaired myeloid lineage differentiation. Interestingly, this defect arises not in granulocyte-monocyte progenitors, but in HSPCs. Gata2b-deficient HSPCs showed impaired progression of the myeloid transcriptional program, concomitant with increased coexpression of lymphoid genes. This resulted in a decrease in myeloid-programmed progenitors and a relative increase in lymphoid-programmed progenitors. This shift in the lineage output could function as an escape mechanism to avoid a block in lineage differentiation. Our study helps to deconstruct the functions of GATA2 during hematopoiesis and shows that lineage differentiation flows toward a lymphoid lineage in the absence of Gata2b.",

author = "Emanuele Gioacchino and Cansu Koyunlar and Joke Zink and {de Looper}, Hans and {de Jong}, Madelon and Tomasz Dobrzycki and Mahony, {Christopher B.} and Remco Hoogenboezem and Dennis Bosch and {van Strien}, {Paulina M.H.} and {van Royen}, {Martin E.} and French, {Pim J.} and Eric Bindels and Gussinklo, {Kirsten J.} and Rui Monteiro and Touw, {Ivo P.} and {de Pater}, Emma",

note = "Funding Information: The authors thank members of the E.d.P., I.P.T., Raaijmakers, and Schneider-Kramann laboratories for helpful discussions; Tom Cupe-do (Erasmus MC) and Elaine Dzierzak (University of Edinburgh) for careful reading of the manuscript; and the Experimental Animal Facility of Erasmus MC for animal husbandry and the Erasmus Optical Imaging Center for confocal microscopy services. The visual abstract was created with BioRender.com. This research was supported by the European Hematology Association (junior nonclinical research fellowship) (E.d.P.), the Dutch Cancer Foundation/Alpe d{\textquoteright}HuZes (SK10321) (E.d.P.), the British Heart Foundation (BHF IBSR fellowship FS/13/50/30436) (R.M. and C.B.M.), the Wellcome Trust (PhD scholarship #WT102345/Z/13/ Z) (T.D.), the Daniel den Hoed Foundation for support of the Cancer Genome Editing Center (I.P.T.), and the Josephine Nefkens Foundation for purchase of the Chromium (103 Genomics) (I.P.T.). Publisher Copyright: {\textcopyright} 2021 by The American Society of Hematology.",

year = "2021",

month = jul,

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doi = "10.1182/bloodadvances.2020002993",

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Gioacchino, E, Koyunlar, C, Zink, J, de Looper, H, de Jong, M, Dobrzycki, T, Mahony, CB, Hoogenboezem, R, Bosch, D, van Strien, PMH, van Royen, ME, French, PJ, Bindels, E, Gussinklo, KJ, Monteiro, R, Touw, IP & de Pater, E 2021, 'Essential role for Gata2 in modulating lineage output from hematopoietic stem cells in zebrafish', Blood Advances, vol. 5, no. 13, pp. 2687-2700. https://doi.org/10.1182/bloodadvances.2020002993

TY - JOUR

T1 - Essential role for Gata2 in modulating lineage output from hematopoietic stem cells in zebrafish

AU - Gioacchino, Emanuele

AU - Koyunlar, Cansu

AU - Zink, Joke

AU - de Looper, Hans

AU - de Jong, Madelon

AU - Dobrzycki, Tomasz

AU - Mahony, Christopher B.

AU - Hoogenboezem, Remco

AU - Bosch, Dennis

AU - van Strien, Paulina M.H.

AU - van Royen, Martin E.

AU - French, Pim J.

AU - Bindels, Eric

AU - Gussinklo, Kirsten J.

AU - Monteiro, Rui

AU - Touw, Ivo P.

AU - de Pater, Emma

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PY - 2021/7/13

Y1 - 2021/7/13

N2 - The differentiation of hematopoietic stem cells (HSCs) is tightly controlled to ensure a proper balance between myeloid and lymphoid cell output. GATA2 is a pivotal hematopoietic transcription factor required for generation and maintenance of HSCs. GATA2 is expressed throughout development, but because of early embryonic lethality in mice, its role during adult hematopoiesis is incompletely understood. Zebrafish contains 2 orthologs of GATA2: Gata2a and Gata2b, which are expressed in different cell types. We show that the mammalian functions of GATA2 are split between these orthologs. Gata2bdeficient zebrafish have a reduction in embryonic definitive hematopoietic stem and progenitor cell (HSPC) numbers, but are viable. This allows us to uniquely study the role of GATA2 in adult hematopoiesis. gata2b mutants have impaired myeloid lineage differentiation. Interestingly, this defect arises not in granulocyte-monocyte progenitors, but in HSPCs. Gata2b-deficient HSPCs showed impaired progression of the myeloid transcriptional program, concomitant with increased coexpression of lymphoid genes. This resulted in a decrease in myeloid-programmed progenitors and a relative increase in lymphoid-programmed progenitors. This shift in the lineage output could function as an escape mechanism to avoid a block in lineage differentiation. Our study helps to deconstruct the functions of GATA2 during hematopoiesis and shows that lineage differentiation flows toward a lymphoid lineage in the absence of Gata2b.

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ER -

Essential role for Gata2 in modulating lineage output from hematopoietic stem cells in zebrafish

Abstract

Bibliographical note

ASJC Scopus subject areas

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