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Heterozygous germline <jats:italic>GATA2<\/jats:italic> mutations result in a syndrome characterized by immunodeficiency, bone marrow failure and predispositions to myelodysplastic syndrome (MDS) and acute myeloid leukaemia. Clinical symptoms in these patients are diverse and mechanisms driving GATA2\u2010related phenotypes are largely unknown. To explore the impact of GATA2 haploinsufficiency on haematopoiesis, we generated a zebrafish model carrying a heterozygous mutation of <jats:italic>gata2b<\/jats:italic> (<jats:italic>gata2b<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup>), an orthologue of <jats:italic>GATA2<\/jats:italic>. Morphological analysis revealed myeloid and erythroid dysplasia in <jats:italic>gata2b<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> kidney marrow. Because Gata2b could affect both transcription and chromatin accessibility during lineage differentiation, this was assessed by single\u2010cell (sc) RNA\u2010seq and single\u2010nucleus (sn) ATAC\u2010seq. Sn\u2010ATAC\u2010seq showed that the co\u2010accessibility between the transcription start site (TSS) and a \u22123.5\u20134.1\u2009kb putative enhancer was more robust in <jats:italic>gata2b<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> zebrafish HSPCs compared to wild type, increasing <jats:italic>gata2b<\/jats:italic> expression and resulting in higher genome\u2010wide Gata2b motif use in HSPCs. As a result of increased accessibility of the <jats:italic>gata2b<\/jats:italic> locus, <jats:italic>gata2b<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> chromatin was also more accessible during lineage differentiation. scRNA\u2010seq data revealed myeloid differentiation defects, that is, impaired cell cycle progression, reduced expression of <jats:italic>cebpa<\/jats:italic> and <jats:italic>cebpb<\/jats:italic> and increased signatures of ribosome biogenesis. These data also revealed a differentiation delay in erythroid progenitors, aberrant proliferative signatures and down\u2010regulation of <jats:italic>Gata1a<\/jats:italic>, a master regulator of erythropoiesis, which worsened with age. These findings suggest that cell\u2010intrinsic compensatory mechanisms, needed to obtain normal levels of Gata2b in heterozygous HSPCs to maintain their integrity, result in aberrant lineage differentiation, thereby representing a critical step in the predisposition to MDS.<\/jats:p>","DOI":"10.1111\/bjh.19585","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T07:55:23Z","timestamp":1718697323000},"page":"580-593","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["<i>GATA2<\/i> heterozygosity causes an epigenetic feedback mechanism resulting in myeloid and erythroid dysplasia"],"prefix":"10.1111","volume":"205","author":[{"given":"Emanuele","family":"Gioacchino","sequence":"first","affiliation":[{"name":"Department of Hematology Erasmus MC Cancer Institute  Rotterdam The 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