Gata2b haploinsufficiency causes aberrant transcriptional signatures in HSPCs resulting in myeloid and erythroid dysplasia in zebrafish

Gioacchino, E.; Koyunlar, C.; Zink, J.; de Looper, H.; Gussinklo, K. J.; Hoogenboezem, R.; Bosch, D.; Bindels, E.; Touw, I. P.; de Pater, E.

doi:10.1101/2021.10.29.466416

bioRxiv · 10.1101/2021.10.29.466416

Gata2b haploinsufficiency causes aberrant transcriptional signatures in HSPCs resulting in myeloid and erythroid dysplasia in zebrafish

Gioacchino, E.·Koyunlar, C.·Zink, J.·de Looper, H.·Gussinklo, K. J.·Hoogenboezem, R.·Bosch, D.·Bindels, E.·Touw, I. P.·de Pater, E.

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Abstract

The transcription factor GATA2 has pivotal roles in hematopoiesis. Germline GATA2 mutations in patients result in GATA2 haploinsufficiency syndrome characterized by immunodeficiency, bone marrow failure, and predispositions to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Clinical symptoms in GATA2 patients are diverse and mechanisms driving GATA2 related phenotypes largely unknown. To explore the impact of GATA2 haploinsufficiency on hematopoiesis, we generated a zebrafish model carrying a heterozygous mutation of gata2b (gata2b+/-), an orthologue of GATA2. Morphological analysis revealed myeloid and erythroid dysplasia in gata2b+/- kidney marrow (KM). single nucleus (sn)-ATAC-seq showed that the co-accessibility between the transcription start site (TSS) and a +3.5-4.1kb enhancer was more robust in gata2b+/- zebrafish HSPCs compared to wild type, increasing gata2b expression. This is suggestive of an auto-regulatory feedback mechanism, where gata2b expression remains at sufficient levels after the loss of a single allele to maintain the HSPC pool. As a result, gata2b+/- chromatin is also more accessible in the erythroid and myeloid lineage, causing several defects. scRNA-seq data revealed a differentiation delay in erythroid progenitors, hallmarked by downregulation of intrinsic signals like cytoskeletal transcripts, aberrant proliferative signatures, and downregulation of Gata1a, a master regulator of erythropoiesis, likely preceding erythroid dysplasia. This shows that the cell intrinsic compensatory mechanisms for the maintenance of normal levels of Gata2b to maintain HSPC integrity result in aberrant lineage differentiation and a preleukemia syndrome.

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Gioacchino, E., Koyunlar, C., Zink, J., de Looper, H., Gussinklo, K. J., Hoogenboezem, R., Bosch, D., Bindels, E., Touw, I. P., de Pater, E.. 2021-10-29. Gata2b haploinsufficiency causes aberrant transcriptional signatures in HSPCs resulting in myeloid and erythroid dysplasia in zebrafish. https://doi.org/10.1101/2021.10.29.466416

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