Dynamics of GATA transcription factor expression during erythroid differentiation

Leonard, Mark; Brice, M; Engel, JD; Papayannopoulou, T

doi:10.1182/blood.v82.4.1071.bloodjournal8241071

Cited by 44 publications

(48 citation statements)

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“…In experiments involving the over‐expression of another member of the GATA family, GATA‐2, erythroid differentiation was blocked leading to continued proliferation of cells (Briegel et al ., 1993). Like GATA‐6 in the embryonic heart lineage (Laverriere et al ., 1994; this study), GATA‐2 expression drops as haematopoietic progenitors differentiate (Briegel et al ., 1993; Leonard et al ., 1993; Nagai et al ., 1994). In the case of embryos injected with GATA‐6 mRNA, it would appear that terminal cardiomyocyte differentiation is prevented until the exogenous mRNA and protein turn over.…”

Section: Discussionmentioning

confidence: 99%

Over-expression of GATA-6 in Xenopus embryos blocks differentiation of heart precursors

Gove

1997

The EMBO Journal

109

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Xenopus GATA-6 transcripts are first detected at the beginning of gastrulation in the mesoderm, and subsequent domains of expression include the field of cells shown to have heart-forming potential. In this region, GATA-6 expression continues only in those cells that go on to form the heart; however, a decrease occurs prior to terminal differentiation. Artificial elevation of GATA-6, but not GATA-1, prevents expression of both cardiac actin and heart-specific myosin light chain. This effect is heart-specific because cardiac actin expression is unaffected in somites. Expression of the earlier marker XNkx-2.5 was unaffected and morphological development of the heart was initiated independently of the establishment of the contractile machinery. We conclude that a reduction in the level of GATA-6 is important for the progression of the cardiomyogenic differentiation programme and that GATA-6 may act to maintain heart cells in the precursor state. At later stages, when the elevated GATA-6 levels had decayed, differentiation ensued but the number of cells contributing to the myocardium had increased, suggesting either that the blocked cells had proliferated or that additional cells had been recruited.

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Section: Discussionmentioning

confidence: 99%

Over-expression of GATA-6 in Xenopus embryos blocks differentiation of heart precursors

Gove

1997

The EMBO Journal

109

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“…By contrast, major progress has been made in understanding the mechanisms that control Kit expression. GATA2, which is expressed prior to GATA1 in HSPCs and in early erythroid precursors (Leonard et al, 1993;Weiss et al, 1994), directly activates Kit transcription (Gao et al, 2013;Jing et al, 2008;Lecuyer et al, 2002) and, as is often the case with GATA2, functions at chromatin sites with the basic helix-loop-helix transcription factor stem cell leukemia (Scl)/T-cell acute lymphocytic leukemia 1 (TAL1) and its associated factors, including the LIM domain proteins Ldb1 and Lmo2 (Hewitt et al, 2016;Hoang et al, 2016;Lecuyer et al, 2002;Wadman et al, 1997;Wozniak et al, 2008) (Fig. 2).…”

Section: Stem Cell Factor Synthesis and Mechanisms Of Actionmentioning

confidence: 99%

Mechanisms of erythrocyte development and regeneration: implications for regenerative medicine and beyond

et al. 2018

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Hemoglobin-expressing erythrocytes (red blood cells) act as fundamental metabolic regulators by providing oxygen to cells and tissues throughout the body. Whereas the vital requirement for oxygen to support metabolically active cells and tissues is well established, almost nothing is known regarding how erythrocyte development and function impact regeneration. Furthermore, many questions remain unanswered relating to how insults to hematopoietic stem/progenitor cells and erythrocytes can trigger a massive regenerative process termed 'stress erythropoiesis' to produce billions of erythrocytes. Here, we review the cellular and molecular mechanisms governing erythrocyte development and regeneration, and discuss the potential links between these events and other regenerative processes.

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“…GATA-2 is expressed in erythroid precursors (Leonard et al, 1993;Weiss et al, 1994), and as GATA-1 expression rises, it represses Gata2 transcription through a GATA switch mechanism Grass et al, 2003). However, the consequences of premature GATA-2 loss on erythroid precursor function are unclear.…”

Section: Gata2 −77 Enhancer-dependent Erythroid Maturation In Vivo Anmentioning

confidence: 99%

Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program

Mehta

Johnson

Gào

et al. 2017

Blood

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GATA-2 levels must be stringently regulated to ensure normal hematopoiesis, and human GATA-2 mutations cause hematologic disorders. GATA-2-regulated enhancers differentially control Gata2 expression in hematopoietic stem/progenitor cells and are essential for hematopoiesis and embryonic development. Mechanisms underlying how the enhancers control Gata2 expression and GATA-2 instigated genetic networks in a cell-specific manner are not completely understood. Targeted deletion of an intronic Gata2 enhancer 9.5 kb downstream of the transcription start site (+9.5) abrogates HSC genesis in the aorta-gonad-mesonephros (AGM) region (Gao et al., JEM, 2013). By contrast, the -77 kb enhancer (-77) activates transcription in myeloid progenitors, and its deletion impairs progenitor differentiation (Johnson et al., Science Advances, 2015). To dissect relationships between the enhancers, we developed a compound heterozygous (CH) mouse model bearing +9.5 and -77 enhancer mutations on different Gata2 alleles. While the CH embryos were alive at E13.5, nearly all died by E14.5 (p = 3.58 x 10-5). Flow cytometric analyses and embryo confocal imaging demonstrated that CH embryos have modestly reduced HSC numbers in the fetal liver (2.9-fold) and the AGM (41%, p = 7.8 x 10-5), which was comparable to +9.5+/- embryos. Thus, -77 does not genetically interact with +9.5 to control HSC emergence. Flow cytometric analysis revealed that Lin-Sca1-Kit+ myelo-erythroid progenitors were 6.6-fold lower in CH vs. WT embryos (p = 1.8 x 10-11), with the difference involving disproportionate losses of GMP (8.6-fold; p = 3.7 x 10-6) and MEP (379-fold; p = 3.2 x 10-9). By contrast, +9.5+/- fetal livers had 2-fold fewer myeloid progenitors, which involved similar reductions of CMP (2.1-fold; p = 1 x 10-6), GMP (2.6-fold; p = 0.0007) and MEP (1.9-fold; p = 0.002). Consistent with the myelo-erythroid progenitor reductions and MEP depletion, CH fetal livers lacked BFU-E (p < 0.001) and CFU-GEMM (p < 0.001) in a colony assay. These results illustrate a genetic interaction between +9.5 and -77 in progenitors, but not HSCs, and a new paradigm in which both enhancers must reside on a single allele to generate MEPs. As erythroid precursor cells express GATA-2, we tested whether the -77 deletion impairs erythroid maturation due to a reduction in myelo-erythroid progenitors or due to a cell-autonomous requirement of the enhancer in erythroid precursors. -77-/- E14.5 fetal livers were pale and smaller than WT counterparts, and -77-/- fetal liver cellularity was reduced 7.2-fold (5.3 x 10-4). When liver size was taken into account, there was little difference in the number of E14.5 R1 cells in -77-/- liver vs. WT littermates (p = 0.31). However, -77-/- R2-R5 cells declined sharply (R2, 8.2-fold, p = 0.004; R3, 14-fold, p < 10-5; R4, 9.7-fold, p = 0.002; R5, 14-fold, p = 0.087). The mutant R1 cells were defective in forming BFU-Es and CFU-Es. Analysis of transcriptomes of purified 77-/- and WT R1 cells from E14.5 fetal livers revealed 2805 and 2519 upregulated and downregulated (p < 0.05) genes, respectively, in -77-/- R1 cells. The -77 enhancer conferred GATA-2 expression, which strongly upregulated GATA-1 and therefore a large GATA-1 target gene cohort. A comparison of WT and -77-/- R1 cell transcriptomes with those of early (Tgbfr3low) and late (Tgbfr3high) BFU-Es (Gao et al., Blood, 2016) revealed a -77-/- R1 signature that correlated with the early BFU-E signature (r = 0.73, p < 10-4) and negatively correlated with the late BFU-E signature (r = -0.42, p = 4 x 10-4) differing from WT cells. In addition to GATA-1 target gene alterations, 253 of the -77-activated genes were not GATA-1-regulated in the G1E-ER-GATA-1 system. These genes included Ryk, which encodes a non-canonical Wnt receptor, and had not been studied in erythroid cells. Two Ryk shRNAs significantly decreased BFU-Es and CFU-GMs in lineage-depleted fetal liver cells. Ongoing studies are integrating Ryk function into signaling circuits that control erythroid maturation and analyzing other -77-regulated targets predicted to constitute new regulators of erythroid cell maturation/function. Thus, loss of the -77 enhancer creates multi-faceted defects in erythroid precursors, involving deficiencies of constituents of signaling and transcriptional circuitry required to enable and drive erythroid maturation. Figure Figure. Disclosures No relevant conflicts of interest to declare.

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Dynamics of GATA transcription factor expression during erythroid differentiation

Cited by 44 publications

References 0 publications

Over-expression of GATA-6 in Xenopus embryos blocks differentiation of heart precursors

Over-expression of GATA-6 in Xenopus embryos blocks differentiation of heart precursors

Mechanisms of erythrocyte development and regeneration: implications for regenerative medicine and beyond

Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program

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