<i>Gata2</i> is required for HSC generation and survival

Pater, Emma de; Kaimakis, Polynikis; Vink, Chris S.; Yokomizo, Tomomasa; Yamada-Inagawa, Tomoko; Linden, Reinier van der; Kartalaei, Parham Solaimani; Camper, Sally A.; Speck, Nancy A.; Dzierzak, Elaine

doi:10.1084/jem.20130751

Cited by 218 publications

(234 citation statements)

References 35 publications

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“…A single protein, GATA-2, governs hematopoietic stem cell (HSC) genesis from hemogenic endothelium in the aorta gonad mesonephros (AGM) region of the embryo and development of the hematopoietic system (de Pater et al, 2013; Tsai et al, 1994). GATA-2 also controls proliferation/survival of hematopoietic progenitors (Tsai and Orkin, 1997).…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic Signaling Mechanism Revealed from a Stem/Progenitor Cell Cistrome

et al. 2015

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SUMMARY Thousands of cis-elements in genomes are predicted to have vital functions. While conservation, activity in surrogate assays, polymorphisms, and disease mutations provide functional clues, deletion from endogenous loci constitutes the gold-standard test. A GATA-2-binding, Gata2 intronic cis-element (+9.5) required for hematopoietic stem cell genesis in mice is mutated in a human immunodeficiency syndrome. As +9.5 is the only cis-element known to mediate stem cell genesis, we devised a strategy to identify functionally comparable enhancers (“+9.5-like”) genome-wide. Gene editing revealed +9.5-like activity to mediate GATA-2 occupancy, chromatin opening, and transcriptional activation. A +9.5-like element resided in Samd14, which encodes a protein of unknown function. Samd14 increased hematopoietic progenitor levels/activity, promoted signaling by a pathway vital for hematopoietic stem/progenitor cell regulation (Stem Cell Factor/c-Kit), and c-Kit rescued Samd14 loss-of-function phenotypes. Thus, the hematopoietic stem/progenitor cell cistrome revealed a mediator of a signaling pathway that has broad importance for stem/progenitor cell biology.

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Section: Introductionmentioning

confidence: 99%

Hematopoietic Signaling Mechanism Revealed from a Stem/Progenitor Cell Cistrome

et al. 2015

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“…Mouse embryo lacking Gata2 died at an early stage due to the severe anemia (Gao et al., 2013, Lim et al., 2012, Ling et al., 2004, Tsai et al., 1994). Notably, mouse HECs without Gata2 failed to produce long-term repopulating HSCs due to an impaired EHT (de Pater et al., 2013). We have also demonstrated that human embryonic stem cells (hESCs) with GATA2 deficiency exhibited a reduced EHT during blood differentiation (Huang et al., 2015).…”

Section: Introductionmentioning

confidence: 99%

Generation and Analysis of GATA2 w/eGFP Human ESCs Reveal ITGB3/CD61 as a Reliable Marker for Defining Hemogenic Endothelial Cells during Hematopoiesis

Huang

Gao

et al. 2016

Stem Cell Reports

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SummaryThe transition from hemogenic endothelial cells (HECs) to hematopoietic stem/progenitor cells (HS/PCs), or endothelial to hematopoietic transition (EHT), is a critical step during hematopoiesis. However, little is known about the molecular determinants of HECs due to the challenge in defining HECs. We report here the generation of GATA2w/eGFP reporter in human embryonic stem cells (hESCs) to mark cells expressing GATA2, a critical gene for EHT. We show that during differentiation, functional HECs are almost exclusively GATA2/eGFP+. We then constructed a regulatory network for HEC determination and also identified a panel of positive or negative surface markers for discriminating HECs from non-hemogenic ECs. Among them, ITGB3 (CD61) precisely labeled HECs both in hESC differentiation and embryonic day 10 mouse embryos. These results not only identify a reliable marker for defining HECs, but also establish a robust platform for dissecting hematopoiesis in vitro, which might lead to the generation of HSCs in vitro.

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“…GATA-2 is expressed predominantly in hematopoietic stem/progenitor cells (HSPCs), mast cells, endothelial cells, and neurons (4)(5)(6)(7)(8). Through its actions to induce HSC generation (9,10) and to regulate HSPC function (11)(12)(13), GATA-2 mediates multilineage hematopoiesis. Mutations that alter the GATA2 coding region (14)(15)(16) or an essential cis element 9.5 kb downstream of the Gata2 1S promoter (ϩ9.5 site) (17,18) cause a primary immunodeficiency syndrome (MonoMAC) commonly associated with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).…”

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confidence: 99%

Epigenetic Determinants of Erythropoiesis: Role of the Histone Methyltransferase SetD8 in Promoting Erythroid Cell Maturation and Survival

DeVilbiss

Sanalkumar

Hall

et al. 2015

Molecular and Cellular Biology

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Erythropoiesis, in which committed progenitor cells generate millions of erythrocytes daily, involves dramatic changes in the chromatin structure and transcriptome of erythroblasts, prior to their enucleation. While the involvement of the master-regulatory transcription factors GATA binding protein 1 (GATA-1) and GATA-2 in this process is established, the mechanistic contributions of many chromatin-modifying/remodeling enzymes in red cell biology remain enigmatic. We demonstrated that SetD8, a histone methyltransferase that catalyzes monomethylation of histone H4 at lysine 20 (H4K20me1), is a context-dependent GATA-1 corepressor in erythroid cells. To determine whether SetD8 controls erythroid maturation and/or function, we used a small hairpin RNA (shRNA)-based loss-of-function strategy in a primary murine erythroblast culture system. In this system, SetD8 promoted erythroblast maturation and survival, and this did not involve upregulation of the established regulator of erythroblast survival Bcl-x L . SetD8 catalyzed H4K20me1 at a critical Gata2 cis element and restricted occupancy by an enhancer of Gata2 transcription, Scl/TAL1, thereby repressing Gata2 transcription. Elevating GATA-2 levels in erythroid precursors yielded a maturation block comparable to that induced by SetD8 downregulation. As lowering GATA-2 expression in the context of SetD8 knockdown did not rescue erythroid maturation, we propose that SetD8 regulation of erythroid maturation involves multiple target genes. These results establish SetD8 as a determinant of erythroid cell maturation and provide a framework for understanding how a broadly expressed histone-modifying enzyme mediates cell-type-specific GATA factor function.T he capacity of stem and progenitor cells to generate multiple cell lineages is orchestrated by cell-type-specific transcription factors that instigate lineage-specific genetic networks. These factors function with a cadre of broadly expressed transcription factors and coregulators, including chromatin-remodeling and -modifying enzymes. Cell-type-specific factors endow broadly expressed factors with activities important for establishing and/or maintaining the specialized transcriptome. Despite this paradigm, the functions of many broadly expressed chromatin-remodeling and -modifying enzymes have not been investigated in cell typespecific contexts. Considering the feasibility of devising smallmolecule strategies to target enzymes, it is instructive to identify enzymatic components mediating important biological processes. We have been addressing this problem by asking how GATA factors with specialized expression patterns and functions utilize broadly expressed coregulators to mediate cellular transitions required for development of hematopoietic stem cells (HSCs), progenitors, and differentiated progeny, including the erythrocyte.The family of dual zinc finger GATA transcription factors (1) recognize DNA with a WGATAR consensus (2, 3). GATA-2 is expressed predominantly in hematopoietic stem/progenitor cells (HSPCs), mast c...

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Gata2 is required for HSC generation and survival

Abstract: GATA2 function is essential for the generation of HSCs during the stage of endothelial-to-hematopoietic cell transition and thereafter for HSC survival

Cited by 218 publications

References 35 publications

Hematopoietic Signaling Mechanism Revealed from a Stem/Progenitor Cell Cistrome

Hematopoietic Signaling Mechanism Revealed from a Stem/Progenitor Cell Cistrome

Generation and Analysis of GATA2 w/eGFP Human ESCs Reveal ITGB3/CD61 as a Reliable Marker for Defining Hemogenic Endothelial Cells during Hematopoiesis

Epigenetic Determinants of Erythropoiesis: Role of the Histone Methyltransferase SetD8 in Promoting Erythroid Cell Maturation and Survival

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