GATA2 is required for HSC generation and survival

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

doi:10.1016/j.exphem.2013.05.070

Cited by 24 publications

(41 citation statements)

References 20 publications

(28 reference statements)

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“…By contrast, gata2a um27 mutants lack trunk circulation (Zhu et al, 2011) and experience hemorrhages (supplementary material Fig. S1), consistent with the consequences of vascular endothelial deletion of Gata2 in mice (de Pater et al, 2013;Johnson et al, 2012;Lim et al, 2012).…”

Section: Gata2b Is Required For Hsc Formationsupporting

confidence: 74%

“…Targeted deletion of Gata2 within the endothelium results in edema, hemorrhage and loss of functional HSCs (de Pater et al, 2013;Johnson et al, 2012;Lim et al, 2012). In addition, GATA2 serves iterative roles in early vascular cells and their hemogenic progeny (de Pater et al, 2013). GATA2 is required within the endothelium for the expression of Runx1 (Gao et al, 2013) that is essential for EHT (Chen et al, 2009;Kissa and Herbomel, 2010;Lancrin et al, 2009), and this is likely to be through direct regulation of a hemogenic endothelial-specific Runx1 enhancer (Nottingham et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Gata2b is a restricted early regulator of hemogenic endothelium in the zebrafish embryo

et al. 2015

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The adult blood system is established by hematopoietic stem cells (HSCs), which arise during development from an endothelial-tohematopoietic transition of cells comprising the floor of the dorsal aorta. Expression of aortic runx1 has served as an early marker of HSC commitment in the zebrafish embryo, but recent studies have suggested that HSC specification begins during the convergence of posterior lateral plate mesoderm (PLM), well before aorta formation and runx1 transcription. Further understanding of the earliest stages of HSC specification necessitates an earlier marker of hemogenic endothelium. Studies in mice have suggested that GATA2 might function at early stages within hemogenic endothelium. Two orthologs of Gata2 exist in zebrafish: gata2a and gata2b. Here, we report that gata2b expression initiates during the convergence of PLM, becoming restricted to emerging HSCs. We observe Notch-dependent gata2b expression within the hemogenic subcompartment of the dorsal aorta that is in turn required to initiate runx1 expression. Our results indicate that Gata2b functions within hemogenic endothelium from an early stage, whereas Gata2a functions more broadly throughout the vascular system.

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Section: Gata2b Is Required For Hsc Formationsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Gata2b is a restricted early regulator of hemogenic endothelium in the zebrafish embryo

et al. 2015

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“…The molecular regulation of this remarkable developmental transition is poorly understood, but would likely involve a resetting of the transcriptional program of the endothelium to that of hematopoietic progenitors. In agreement with this notion, the transcription factors Runx1 (7) and Gata2 (13) have been shown to be critical for this transition. It remains unclear what gene expression programs these transcription factors regulate, and whether chromatin regulators also play a role in this transition.…”

mentioning

confidence: 56%

“…In addition, we identified very significant enrichments for genes regulated by Gata2 and Runx1-Runx1t1 (Fig. S6 B and C), and both of these transcription factors are key regulators of the emergence of HSPCs (7,13).…”

Section: Transcriptional Profiling Of the Chd1 Mutant Endothelium Revmentioning

confidence: 91%

Emergence of hematopoietic stem and progenitor cells involves a Chd1-dependent increase in total nascent transcription

Koh

Lizama

Wong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Lineage specification during development involves reprogramming of transcriptional states, but little is known about how this is regulated in vivo. The chromatin remodeler chomodomain helicase DNA-binding protein 1 (Chd1) promotes an elevated transcriptional output in mouse embryonic stem cells. Here we report that endothelial-specific deletion of Chd1 leads to loss of definitive hematopoietic progenitors, anemia, and lethality by embryonic day (E)15.5. Mutant embryos contain normal numbers of E10.5 intraaortic hematopoietic clusters that express Runx1 and Kit, but these clusters undergo apoptosis and fail to mature into blood lineages in vivo and in vitro. Hematopoietic progenitors emerging from the aorta have an elevated transcriptional output relative to structural endothelium, and this elevation is Chd1-dependent. In contrast, hematopoietic-specific deletion of Chd1 using Vav-Cre has no apparent phenotype. Our results reveal a new paradigm of regulation of a developmental transition by elevation of global transcriptional output that is critical for hemogenesis and may play roles in other contexts.

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“…In addition, the small number of HSCs generated from +9.5 −/− AGM undergo apoptosis and lack LT activity, indicating that the +9.5 element also confers LT-HSC survival (25); a similar conclusion emerged from analysis of a conditional Gata2 KO mouse (52). The +9.5 site confers maximal Gata2 expression in the AGM and definitive hematopoietic precursors in the fetal liver (5,25).…”

Section: Requirements For Assembly Of An Intronic Enhancer Complexmentioning

confidence: 93%

Mechanism governing a stem cell-generating cis -regulatory element

Sanalkumar

Johnson

Gào

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The unremitting demand to replenish differentiated cells in tissues requires efficient mechanisms to generate and regulate stem and progenitor cells. Although master regulatory transcription factors, including GATA binding protein-2 (GATA-2), have crucial roles in these mechanisms, how such factors are controlled in developmentally dynamic systems is poorly understood. Previously, we described five dispersed Gata2 locus sequences, termed the −77, −3.9, −2.8, −1.8, and +9.5 GATA switch sites, which contain evolutionarily conserved GATA motifs occupied by GATA-2 and GATA-1 in hematopoietic precursors and erythroid cells, respectively. Despite common attributes of transcriptional enhancers, targeted deletions of the −2.8, −1.8, and +9.5 sites revealed distinct and unpredictable contributions to Gata2 expression and hematopoiesis. Herein, we describe the targeted deletion of the −3.9 site and mechanistically compare the −3.9 site with other GATA switch sites. The −3.9 −/− mice were viable and exhibited normal Gata2 expression and steady-state hematopoiesis in the embryo and adult. We established a Gata2 repression/reactivation assay, which revealed unique +9.5 site activity to mediate GATA factor-dependent chromatin structural transitions. Loss-of-function analyses provided evidence for a mechanism in which a mediator of long-range transcriptional control [LIM domain binding 1 (LDB1)] and a chromatin remodeler [Brahma related gene 1 (BRG1)] synergize through the +9.5 site, conferring expression of GATA-2, which is known to promote the genesis and survival of hematopoietic stem cells.cis element | HSCs W hereas proximal promoter sequences assemble the basal transcriptional machinery and RNA polymerase, distant cis-regulatory elements often confer tissue-specific or contextdependent transcriptional regulation. Enhancer elements reside many kilobases upstream or downstream of a promoter or within introns, and extensive efforts have focused on elucidating "action-at-a-distance" mechanisms (1). Long-range transcriptional control involves physical interactions between proteins bound at distal regions and promoter sequences and higher order structural transitions, including subnuclear relocalization of target loci (2-4). Given the high frequency of long-range mechanisms at mammalian loci and the mutations that disrupt the function of such elements in pathological conditions, elucidating the underlying mechanisms in development,

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GATA2 is required for HSC generation and survival

Cited by 24 publications

References 20 publications

Gata2b is a restricted early regulator of hemogenic endothelium in the zebrafish embryo

Gata2b is a restricted early regulator of hemogenic endothelium in the zebrafish embryo

Emergence of hematopoietic stem and progenitor cells involves a Chd1-dependent increase in total nascent transcription

Mechanism governing a stem cell-generating cis -regulatory element

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