Proximity among Distant Regulatory Elements at the β-Globin Locus Requires GATA-1 and FOG-1

Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Molecular Cell (Impact Factor: 14.46). 03/2005; 17(3):453-62. DOI: 10.1016/j.molcel.2004.12.028
Source: PubMed

ABSTRACT Recent evidence suggests that long-range enhancers and gene promoters are in close proximity, which might reflect the formation of chromatin loops. Here, we examined the mechanism for DNA looping at the beta-globin locus. By using chromosome conformation capture (3C), we show that the hematopoietic transcription factor GATA-1 and its cofactor FOG-1 are required for the physical interaction between the beta-globin locus control region (LCR) and the beta-major globin promoter. Kinetic studies reveal that GATA-1-induced loop formation correlates with the onset of beta-globin transcription and occurs independently of new protein synthesis. GATA-1 occupies the beta-major globin promoter normally in fetal liver erythroblasts from mice lacking the LCR, suggesting that GATA-1 binding to the promoter and LCR are independent events that occur prior to loop formation. Together, these data demonstrate that GATA-1 and FOG-1 are essential anchors for a tissue-specific chromatin loop, providing general insights into long-range enhancer function.

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    • "The importance of direct contacts between enhancer-and promoterbound proteins for E–P communication was also demonstrated in the human beta-globin gene domain. Here, the erythroid transcription factor GATA-1 mediates looping between the LCR (the major regulatory element of the domain) and the beta-globin gene promoter (Vakoc et al., 2005). GATA-1 binds to the promoter and the LCR and primes the formation of protein complexes that include Ldb1. "
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    ABSTRACT: The eukaryotic genome has an extremely complex spatial organization. The physical distances between regulatory elements of the genome, such as enhancers, promoters, insulators, and CpG-islands, do not necessarily reflect genomic distances. Some remote regulatory elements appear to interact physically with target promoters in the 3D nuclear space. These spatial contacts are thought to play a crucial role in the regulation of transcription. Recent studies performed using 3C (chromosome conformation capture)-based methods, FISH (fluorescence in situ hybridization) coupled with confocal microscopy, and other experimental approaches have revealed that the spatial interactions of distant genomic elements within a folded chromosome are specific and functionally relevant. Additionally, the spatial organization of the eukaryotic genome is linked to the functional compartmentalization of the cell nucleus. In this review, we discuss the current state of research on the functional architecture of the eukaryotic genome. Special emphasis is given to the role of the spatial organization of the genome in establishing communication between enhancers and promoters. The driving forces of the juxtaposition of remote genomic elements are also considered.
    International review of cell and molecular biology 01/2015; 315:183-244. DOI:10.1016/bs.ircmb.2014.11.004 · 4.52 Impact Factor
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    • "Interestingly, reduced FOG1 and NuRD occupancy at the b-globin gene were observed in other studies in which globin loci failed to migrate away from the nuclear periphery (Lee et al. 2011). FOG1 is required for LCR/b-globin looping presumably through GATA1 stabilization or recruitment of other factors (Letting et al. 2004; Pal et al. 2004; Vakoc et al. 2005). Therefore, a challenging question that remains is how looping occurs in cells expressing LDB1D4/5 in which FOG1 recruitment is reduced compared with cells expressing LDB1 FL. "
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    ABSTRACT: Many questions remain about how close association of genes and distant enhancers occurs and how this is linked to transcription activation. In erythroid cells, lim domain binding 1 (LDB1) protein is recruited to the β-globin locus via LMO2 and is required for looping of the β-globin locus control region (LCR) to the active β-globin promoter. We show that the LDB1 dimerization domain (DD) is necessary and, when fused to LMO2, sufficient to completely restore LCR–promoter looping and transcription in LDB1-depleted cells. The looping function of the DD is unique and irreplaceable by heterologous DDs. Dissection of the DD revealed distinct functional properties of conserved subdomains. Notably, a conserved helical region (DD4/5) is dispensable for LDB1 dimerization and chromatin looping but essential for transcriptional activation. DD4/5 is required for the recruitment of the coregulators FOG1 and the nucleosome remodeling and deacetylating (NuRD) complex. Lack of DD4/5 alters histone acetylation and RNA polymerase II recruitment and results in failure of the locus to migrate to the nuclear interior, as normally occurs during erythroid maturation. These results uncouple enhancer–promoter looping from nuclear migration and transcription activation and reveal new roles for LDB1 in these processes.
    Genes & development 06/2014; 28(12):1278-1290. DOI:10.1101/gad.239749.114 · 12.64 Impact Factor
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    • "FOG-1 also interacts with the C-terminal binding protein (CtBP), mainly described as a corepressor and the nucleosome remodelling and histone deacetylase repressive (NuRD) complex and thus makes a link between transcription factors and chromatin modifiers. FOG-1 also activates or represses gene transcription by facilitating binding of GATA factors to DNA [7], recruiting chromatin remodelling complexes [5], [8], or by stabilizing tissue-specific chromatin loops [9]. FOG-1 is expressed at high level in multipotent progenitors, erythroid and megakaryocytic cells, low level in lymphoid and haematopoietic stem cells; it is absent in myeloid lineages [3]. "
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    ABSTRACT: We have identified expression of the gene encoding the transcriptional coactivator FOG-1 (Friend of GATA-1; Zfpm1, Zinc finger protein multitype 1) in B lymphocytes. We found that FOG-1 expression is directly or indirectly dependent on the B cell-specific coactivator OBF-1 and that it is modulated during B cell development: expression is observed in early but not in late stages of B cell development. To directly test in vivo the role of FOG-1 in B lymphocytes, we developed a novel embryonic stem cell recombination system. For this, we combined homologous recombination with the FLP recombinase activity to rapidly generate embryonic stem cell lines carrying a Cre-inducible transgene at the Rosa26 locus. Using this system, we successfully generated transgenic mice where FOG-1 is conditionally overexpressed in mature B-cells or in the entire hematopoietic system. While overexpression of FOG-1 in B cells did not significantly affect B cell development or function, we found that enforced expression of FOG-1 throughout all hematopoietic lineages led to a reduction in the number of circulating eosinophils, confirming and extending to mammals the known function of FOG-1 in this lineage.
    PLoS ONE 04/2014; 9(4):e92836. DOI:10.1371/journal.pone.0092836 · 3.23 Impact Factor
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