Lineage skewing and genome instability underlie marrow failure in a zebrafish model of GATA2 deficiency

Mahony, Christopher B.; Copper, Lucy; Vrljicak, Pavle; Noyvert, Boris; Constantinidou, Chrystala; Browne, Sofia; Pan, Yi; Palles, Claire; Ott, Sascha; Higgs, Martin R.; Monteiro, Rui

doi:10.1016/j.celrep.2023.112571

Cited by 3 publications

(3 citation statements)

References 83 publications

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“…The precise expression regulation of GATA2 has a profound impact on hematopoietic development, as high expression of GATA2 is required for HSC self-renewal and maintenance, while procedural downregulation is imperative to facilitate downstream lineage differentiation. Recent advances in the field in terms of new animal models to understand the precise role of GATA2 in lineage differentiation can significantly contribute to the development of treatments for the life-threatening cytopenias from which the majority of GATA2 deficiency syndrome patients suffer ( Gioacchino, et al, 2021a ; Gioacchino et al, 2021b ; Mahony et al, 2023 ). In recent years, the employment of single cell sequencing technologies resulted in remarkable progress in the comprehension of the molecular regulatory processes governing hematopoietic cell fate determination ( Ranzoni et al, 2021 ; Zeller et al, 2023 ; Zhang et al, 2023 ).…”

Section: Conclusion and Discussionmentioning

confidence: 99%

“…This could be due to the absence of secondary injuries like infections or the fact that mice are bred in a congenic background. Interestingly, these cytopenic phenotypes have been modeled using zebrafish, where homozygous deletion of Gata2b leads to neutropenia ( Gioacchino et al, 2021a ; Avagyan et al, 2021 ), and loss of the intronic enhancer of Gata2a results in monocytopenia and neutropenia ( Dobrzycki et al, 2020 ; Mahony et al, 2023 ), providing direct insights into the molecular effects of GATA2 mutation in blood lineage differentiation in the hematopoietic system. This, however, does not explain why only specific lineages are affected in zebrafish, e.g., the monocyte lineage in Gata2a enhancer mutant zebrafish, while this lineage is unaffected in Gata2b mutant zebrafish.…”

Section: The Role Of Gata2 In Hsc Self-renewal and Differentiationmentioning

confidence: 99%

“…Therefore, there will always be a need for model systems to study human disease. Current zebrafish and mouse models of GATA2 deficiency syndrome were only able to partially phenocopy the lineage differentiation defects observed in patients ( Dobrzycki et al, 2020 ; Abdelfattah et al, 2021 ; Gioacchino et al, 2021a ; Avagyan et al, 2021 ; Gioacchino et al, 2021b ; You et al, 2022 ; Mahony et al, 2023 ). This could be due to significant disparities between animal models and humans concerning adult size, aging and niche components.…”

Section: The Challenges Of Modelling Defects In Cell Fate Determinati...mentioning

confidence: 99%

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The role of GATA2 in adult hematopoiesis and cell fate determination

Peters,

de Pater,

Zhang

2023

Front. Cell Dev. Biol.

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The correct maintenance and differentiation of hematopoietic stem cells (HSC) in bone marrow is vital for the maintenance and operation of the human blood system. GATA2 plays a critical role in the maintenance of HSCs and the specification of HSCs into the different hematopoietic lineages, highlighted by the various defects observed in patients with heterozygous mutations in GATA2, resulting in cytopenias, bone marrow failure and increased chance of myeloid malignancy, termed GATA2 deficiency syndrome. Despite this, the mechanisms underlying GATA2 deficiency syndrome remain to be elucidated. The detailed description of how GATA2 regulates HSC maintenance and blood lineage determination is crucial to unravel the pathogenesis of GATA2 deficiency syndrome. In this review, we summarize current advances in elucidating the role of GATA2 in hematopoietic cell fate determination and discuss the challenges of modeling GATA2 deficiency syndrome.

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Section: Conclusion and Discussionmentioning

confidence: 99%

Section: The Role Of Gata2 In Hsc Self-renewal and Differentiationmentioning

confidence: 99%

Section: The Challenges Of Modelling Defects In Cell Fate Determinati...mentioning

confidence: 99%

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The role of GATA2 in adult hematopoiesis and cell fate determination

Peters,

de Pater,

Zhang

2023

Front. Cell Dev. Biol.

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Protocol for the analysis of hematopoietic lineages in the whole kidney marrow of adult zebrafish

Mahony,

Monteiro

2024

STAR Protocols

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Zebrafish regulatory genomic resources for disease modelling and regeneration

Jimenez Gonzalez,

Baranasic,

Müller

2023

Disease Models &Amp; Mechanisms

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In the past decades, the zebrafish has become a disease model with increasing popularity owing to its advantages that include fast development, easy genetic manipulation, simplicity for imaging, and sharing conserved disease-associated genes and pathways with those of human. In parallel, studies of disease mechanisms are increasingly focusing on non-coding mutations, which require genome annotation maps of regulatory elements, such as enhancers and promoters. In line with this, genomic resources for zebrafish research are expanding, producing a variety of genomic data that help in defining regulatory elements and their conservation between zebrafish and humans. Here, we discuss recent developments in generating functional annotation maps for regulatory elements of the zebrafish genome and how this can be applied to human diseases. We highlight community-driven developments, such as DANIO-CODE, in generating a centralised and standardised catalogue of zebrafish genomics data and functional annotations; consider the advantages and limitations of current annotation maps; and offer considerations for interpreting and integrating existing maps with comparative genomics tools. We also discuss the need for developing standardised genomics protocols and bioinformatic pipelines and provide suggestions for the development of analysis and visualisation tools that will integrate various multiomic bulk sequencing data together with fast-expanding data on single-cell methods, such as single-cell assay for transposase-accessible chromatin with sequencing. Such integration tools are essential to exploit the multiomic chromatin characterisation offered by bulk genomics together with the cell-type resolution offered by emerging single-cell methods. Together, these advances will build an expansive toolkit for interrogating the mechanisms of human disease in zebrafish.

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Lineage skewing and genome instability underlie marrow failure in a zebrafish model of GATA2 deficiency

Cited by 3 publications

References 83 publications

The role of GATA2 in adult hematopoiesis and cell fate determination

The role of GATA2 in adult hematopoiesis and cell fate determination

Protocol for the analysis of hematopoietic lineages in the whole kidney marrow of adult zebrafish

Zebrafish regulatory genomic resources for disease modelling and regeneration

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