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Gata2 loss alters epigenetic priming and gene expression profiles in early myeloid and lymphoid progenitors leading to cytopenias

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Danio rerio

PROVIDER: GSE151232 | GEO | 2021/02/25

REPOSITORIES: GEO

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Gata2 loss alters epigenetic priming and gene expression profiles in early myeloid and lymphoid progenitors leading to cytopenias [RNA-seq]

Project description:Germline heterozygous mutations in GATA2 are associated with a syndrome characterized by cytopenias, atypical infections, and increased risk of hematologic malignancies. Due to embryonic lethality of Gata2-/- mice, the role of germline loss of GATA2 has not been studied in adult hematopoiesis. Here, we generated a zebrafish mutant of gata2b, which in adulthood recapitulated the myelomonocytopenia and B cell lymphopenia of GATA2 syndrome. Using single cell epigenetic and transcriptomic analyses, we showed that loss of gata2b alters chromosome accessibility and results in gene expression changes in both early myeloid and lymphoid progenitors. We found differentiation block with skewing away from the monocytic program in myeloid progenitors in gata2bko zebrafish. In lymphoid progenitors, gata2b loss led to increased lymphoid priming but with incomplete B cell lymphopoiesis. These results place GATA2 in critical junctions of lineage specification in adult hematopoiesis.

2021-02-25 | GSE151231 | GEO

Gata2 loss alters epigenetic priming and gene expression profiles in early myeloid and lymphoid progenitors leading to cytopenias [ATAC-seq]

2021-02-25 | GSE151230 | GEO

Gata2 loss alters epigenetic priming and gene expression profiles in early myeloid and lymphoid progenitors leading to cytopenias

Project description:Gata2 loss alters epigenetic priming and gene expression profiles in early myeloid and lymphoid progenitors leading to cytopenias

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Gata2 loss alters epigenetic priming and gene expression profiles in early myeloid and lymphoid progenitors leading to cytopenias [RNA-seq]

Project description:Gata2 loss alters epigenetic priming and gene expression profiles in early myeloid and lymphoid progenitors leading to cytopenias [RNA-seq]

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Gata2 loss alters epigenetic priming and gene expression profiles in early myeloid and lymphoid progenitors leading to cytopenias [ATAC-seq]

Project description:Gata2 loss alters epigenetic priming and gene expression profiles in early myeloid and lymphoid progenitors leading to cytopenias [ATAC-seq]

| PRJNA635160 | ENA

Single-cell ATAC-seq reveals GATA2-dependent priming defect in myeloid and a maturation bottleneck in lymphoid lineages.

Project description:Germline heterozygous mutations in GATA2 are associated with a syndrome characterized by cytopenias, atypical infections, and increased risk of hematologic malignancies. Here, we generated a zebrafish mutant of gata2b that recapitulated the myelomonocytopenia and B-cell lymphopenia of GATA2 deficiency syndrome. Using single-cell assay for transposase accessible chromatin with sequencing of marrow cells, we showed that loss of gata2b led to contrasting alterations in chromosome accessibility in early myeloid and lymphoid progenitors, associated with defects in gene expression. Within the myeloid lineage in gata2b mutant zebrafish, we identified an attenuated myeloid differentiation with reduced transcriptional priming and skewing away from the monocytic program. In contrast, in early lymphoid progenitors, gata2b loss led to accumulation of B-lymphoid transcription factor accessibility coupled with increased expression of the B-cell lineage-specification program. However, gata2b mutant zebrafish had incomplete B-cell lymphopoiesis with loss of lineage-specific transcription factor accessibility in differentiating B cells, in the context of aberrantly reduced oxidative metabolic pathways. Our results establish that transcriptional events in early progenitors driven by Gata2 are required to complete normal differentiation.

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Transcription factors TCF-1 and GATA3 are key factors for the epigenetic priming of early innate lymphoid progenitors toward distinct cell fates.

Project description:The differentiation of innate lymphoid cells (ILCs) from hematopoietic stem cells needs to go through several multipotent progenitor stages. However, it remains unclear whether the fates of multipotent progenitors are predefined by epigenetic states. Here, we report the identification of distinct accessible chromatin regions in all lymphoid progenitors (ALPs), EILPs, and ILC precursors (ILCPs). Single-cell MNase-seq analyses revealed that EILPs contained distinct subpopulations epigenetically primed toward either dendritic cell lineages or ILC lineages. We found that TCF-1 and GATA3 co-bound to the lineage-defining sites for ILCs (LDS-Is), whereas PU.1 binding was enriched in the LDSs for alternative dendritic cells (LDS-As). TCF-1 and GATA3 were indispensable for the epigenetic priming of LDSs at the EILP stage. Our results suggest that the multipotency of progenitor cells is defined by the existence of a heterogeneous population of cells epigenetically primed for distinct downstream lineages, which are regulated by key transcription factors.

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Project description:The mechanism of lineage commitment from hematopoietic stem cells (HSCs) is not well understood. Although commitment to either the lymphoid or the myeloid lineage is popularly viewed as the first step of lineage restriction from HSCs, this model of hematopoietic differentiation has recently been challenged. The previous identification of multipotent progenitors (MPPs) that can produce lymphocytes and granulocyte/macrophages (GMs) but lacks erythroid differentiation ability suggests the existence of an alternative HSC differentiation program. Contribution to different hematopoietic lineages by these MPPs under physiological conditions, however, has not been carefully examined. In this study, we performed a refined characterization of MPPs by subfractionating three distinct subsets based on Flt3 and vascular cell adhesion molecule 1 expression. These MPP subsets differ in their ability to give rise to erythroid and GM lineage cells but are equally potent in lymphoid lineage differentiation in vivo. The developmental hierarchy of these MPP subsets demonstrates the sequential loss of erythroid and then GM differentiation potential during early hematopoiesis. Our results suggest that the first step of lineage commitment from HSCs is not simply a selection between the lymphoid and the myeloid lineage.

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