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Gottgens B, Nastos A, Kinston S, Piltz S, Delabesse EC, Stanley M et al.. Establishing the transcriptional programme for blood: the SCL stem cell enhancer is regulated by a multiprotein complex containing Ets and GATA factors. EMBO J 21: 3039-3050

University of Cambridge Department of Haematology, Cambridge Institute for Medical Research, Hills Road, Cambridge CB2 2XY, UK.
The EMBO Journal (Impact Factor: 10.75). 07/2002; 21(12):3039-50. DOI: 10.1093/emboj/cdf286
Source: PubMed

ABSTRACT Stem cells are a central feature of metazoan biology. Haematopoietic stem cells (HSCs) represent the best-characterized example of this phenomenon, but the molecular mechanisms responsible for their formation remain obscure. The stem cell leukaemia (SCL) gene encodes a basic helix-loop-helix (bHLH) transcription factor with an essential role in specifying HSCs. Here we have addressed the transcriptional hierarchy responsible for HSC formation by characterizing an SCL 3' enhancer that targets expression to HSCs and endothelium and their bipotential precursors, the haemangioblast. We have identified three critical motifs, which are essential for enhancer function and bind GATA-2, Fli-1 and Elf-1 in vivo. Our results suggest that these transcription factors are key components of an enhanceosome responsible for activating SCL transcription and establishing the transcriptional programme required for HSC formation.

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Available from: Sandra Piltz, Feb 08, 2015
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    • "Among HSCrelated genes, cis-regulatory elements of Scl have been most extensively studied. Tg mouse studies have shown that Scl +19(e) targets expression of a reporter gene to ECs and HPCs at E11.5 (Gottgens et al., 2002). Tamoxifen-inducible CreER T recombinase under the control of Scl +19(e) showed 17% marking within the KSL compartment of FL at E14.5. "
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    ABSTRACT: There has been considerable interest in identifying a cis-regulatory element that targets gene expression to stem cells. Such an element, termed stem cell enhancer, holds the promise of providing important insights into the transcriptional programs responsible for inherent stem cell-specific properties such as self-renewal capacity. The element also serves as a molecular handle for stem cell-specific marking, transgenesis and gene targeting, thereby becoming invaluable to stem cell research. A series of candidate enhancers have been identified for hematopoietic stem cells (HSCs). This review summarizes currently known HSC enhancers with emphasis on an intronic enhancer in the Runx1 gene which is essential for the generation and maintenance of HSCs. The element, named eR1 (+24m), is active specifically in HSCs, but not in progenitors, and is hence the most definitive HSC enhancer.
    Histology and histopathology 01/2015; · 2.24 Impact Factor
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    • "These studies support the conclusion that both Ets and Gata factors play important roles in hematopoietic and endothelial development. Investigation of the transcriptional regulation of Tal1 gene expression has revealed the cooperative interaction between Gata2, Fli1 and Elf1 in transactivation of Tal1 gene expression and hematopoietic development (Gottgens et al., 2002). Similar studies using the Gata2, Fli1 and Tal1 enhancers have shown that Gata factor (Gata2), Ets factor (Fli1), and Scl form a regulatory circuit during early hematopoietic development (Pimanda et al., 2007). "
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    ABSTRACT: Regulatory mechanisms that govern lineage specification of the mesodermal progenitors to become endothelial and hematopoietic cells remain an area of intense interest. Both Ets and Gata factors have been shown to have important roles in the transcriptional regulation in endothelial and hematopoietic cells. We previously reported Etv2 as an essential regulator of vasculogenesis and hematopoiesis. In the present study, we demonstrate that Gata2 is co-expressed and interacts with Etv2 in the endothelial and hematopoietic cells in the early stages of embryogenesis. Our studies reveal that Etv2 interacts with Gata2 in vitro and in vivo. The protein-protein interaction between Etv2 and Gata2 is mediated by the Ets and Gata domains. Using the embryoid body differentiation system, we demonstrate that co-expression of Gata2 augments the activity of Etv2 in promoting endothelial and hematopoietic lineage differentiation. We also identify Spi1 as a common downstream target gene of Etv2 and Gata2. We provide evidence that Etv2 and Gata2 bind to the Spi1 promoter in vitro and in vivo. In summary, we propose that Gata2 functions as a cofactor of Etv2 in the transcriptional regulation of mesodermal progenitors during embryogenesis.
    Developmental Biology 05/2014; 389(2). DOI:10.1016/j.ydbio.2014.02.018 · 3.64 Impact Factor
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    • "Gata1 + Zfpm1 INHIBITION Gata2 (Crispino et al., 1999) Fli1 + Gata2 ACTIVATION Scl (Gottgens et al., 2002) Fli1 ACTIVATION Gata2 (Pimanda et al., 2007b) Scl + Gata1 ACTIVATION Scl (Ogilvy et al., 2007) Scl + Gata2 ACTIVATION Gata2 (Johnson et al., 2012; Khandekar et al., 2007) Scl + Gata1 ACTIVATION Gata1 (Vyas et al., 1999) Gata2 + Scl ACTIVATION Zfpm1 (Wilson et al., 2010; Wilson et al., 2009) Gata2 + Scl ACTIVATION Scl (Ogilvy et al., 2007) Fli1 ACTIVATION Scl (Gottgens et al., 2002) Fli1 ACTIVATION Fli1 (Donaldson et al., 2005) Gata2 ACTIVATION Fli1 (Donaldson et al., 2005) Fli1 ACTIVATION Erg (Thoms et al., 2011) Erg ACTIVATION Fli1 (Pimanda et al., 2007b; Wilson et al., 2010) Erg ACTIVATION Erg (Thoms et al., 2011) Scl + Eto2 INHIBITION Erg (Schuh, 2005; Thoms et al., 2011) Scl + Gata2 ACTIVATION Fli1 (Pimanda et al., 2007b) Gata2 ACTIVATION Erg (Thoms et al., 2011) Runx1 ACTIVATION Runx1 (Nottingham et al., 2007) Pu.1 ACTIVATION Runx1 (Nottingham et al., 2007) Runx1 ACTIVATION Pu.1 (Huang et al., 2008) Gata2 + Scl ACTIVATION Runx1 (Nottingham et al., 2007) Fli1 ACTIVATION Runx1 (Nottingham et al., 2007) Erg ACTIVATION Runx1 (Taoudi et al., 2011) Pu.1 ACTIVATION Pu.1 (Chen et al., 1995) Scl + Gata2 ACTIVATION Eto2 (Wilson et al., 2010; Wilson et al., 2009) Runx1 + Smad6 INHIBITION Runx1 (Pimanda et al., 2007a) Erg ACTIVATION Smad6 (Knezevic et al., 2011) Fli1 ACTIVATION Smad6 (Knezevic et al., 2011) Scl + Gata2 ACTIVATION Smad6 (Knezevic et al., 2011) Erg ACTIVATION Scl (Gottgens et al., 2002; Rainis et al., 2005) Scl + Gata2 ACTIVATION Hhex (Donaldson et al., 2005; Wilson et al., 2009) Gata2 + Hhex INHIBITION Gata2 (Kobayashi-Osaki et al., 2005; Minami et al., 2004) Fli1 ACTIVATION Hhex (Donaldson et al., 2005) Erg ACTIVATION Hhex (Oram et al., 2010) Runx1 ACTIVATION Erg (Thoms et al., 2011; Wilson et al., 2010) Erg ACTIVATION Gata2 (Taoudi et al., 2011) "
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