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: 14.02). 03/2005; 17(3):453-62. DOI: 10.1016/j.molcel.2004.12.028
Source: PubMed


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 02/2015; 315:183-244. DOI:10.1016/bs.ircmb.2014.11.004 · 3.42 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 · 10.80 Impact Factor
    • "One of the best-studied examples regards the mammalian b-globin locus, where transcriptionally reliant long-range interactions occur among a powerful distal enhancer, a locus control region (LCR), and a set of distal promoters located 40–80 kb away. These events are mediated by specific transcription factors including KLF1 and GATA1 (Drissen et al., 2004; Vakoc et al., 2005; Deng et al., 2012). Additionally, many looping events occur between active gene promoters and distal elements that bypass one or more neighboring genes. "
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    ABSTRACT: Compaction of the eukaryotic genome into the confined space of the cell nucleus must occur faithfully throughout each cell cycle to retain gene expression fidelity. For decades, experimental limitations to study the structural organization of the interphase nucleus restricted our understanding of its contributions towards gene regulation and disease. However, within the past few years, our capability to visualize chromosomes in vivo with sophisticated fluorescence microscopy, and to characterize chromosomal regulatory environments via massively-parallel sequencing methodologies have drastically changed how we currently understand epigenetic gene control within the context of three-dimensional nuclear structure. The rapid rate at which information on nuclear structure is unfolding brings challenges to compare and contrast recent observations with historic findings. In this review, we discuss experimental breakthroughs that have influenced how we understand and explore the dynamic structure and function of the nucleus, and how we can incorporate historical perspectives with insights acquired from the ever-evolving advances in molecular biology and pathology. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 06/2014; 229(6). DOI:10.1002/jcp.24508 · 3.84 Impact Factor
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