The role of CTCF in regulating V(D)J recombination

Department of Pathology, New York University School of Medicine, 550 First Avenue, MSB 599, New York, NY 10016, USA.
Current opinion in immunology (Impact Factor: 7.48). 03/2012; 24(2):153-9. DOI: 10.1016/j.coi.2012.01.003
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V(D)J recombination in B and T cells is required for the generation of receptors with a broad spectrum of specificity to foreign antigen. A total number of three immunoglobulin (Ig) and four T cell receptor (Tcr) loci can be targeted by the recombinase enzyme (RAG1/2) in a defined series of recombination events, which drive the progression of B and T cell development. This process is regulated at multiple levels to ensure lineage specific, ordered rearrangement and allelic exclusion. One key component of this is modulation of chromatin looping and locus contraction, which is important in bringing widely separated gene segments into close contact with each other to enable synapse formation for lineage and stage specific V gene rearrangement [2,3,4(•),5,6(•)]. Recent studies provide new insight into looping and its role in these processes. In this review we focus on the contribution of the 11 zinc finger nuclear protein, CTCF, in mediating loop formation and conformational changes that are important for the regulation of Ig and Tcr rearrangement.

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Available from: Julie Chaumeil, Oct 02, 2015
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    • "This protein localizes at the DNase I-hypersensitive sites, open chromatin determinants that are generally common across cell types (Song et al., 2011). There is ample experimental evidence for the role of CTCF in organization of chromatin architecture in particular loci and formation of TADs (Chaumeil and Skok, 2012; Herold et al., 2012; Holwerda and de Laat, 2012; Merkenschlager and Odom, 2013). Although CTCF is recognized as the main architectural protein, information on the involvement of its domains in long-distance interactions is scarce (Figure 3A). "
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    ABSTRACT: Due to advances in genome-wide technologies, consistent distant interactions within chromosomes of higher eukaryotes have been revealed. In particular, it has been shown that enhancers can specifically and directly interact with promoters by looping out intervening sequences, which can be up to several hundred kilobases long. This review is focused on transcription factors that are supposed to be involved in long-range interactions. Available data are in agreement with the model that several known transcription factors and insulator proteins belong to an abundant but poorly studied class of proteins that are responsible for chromosomal architecture.
    Frontiers in Genetics 02/2014; 5:28. DOI:10.3389/fgene.2014.00028
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    • "The IgH locus contains many cis-regulatory elements, including the intergenic control region 1 (IGCR1), the intronic enhancer Eµ and the downstream 3′ regulatory region (3′RR), which are involved in the regulation of the of V(D)J recombination (5–7) and class switch recombination (8). Chromosome topology and nuclear location have been implicated in the control of V(D)J recombination and allelic exclusion (3,9–11). In the early pro-B stage, the IgH locus adopts a central position in the nuclear interior and chromatin looping mediates physical proximity of both ends of the locus (12,13), facilitating recombination of distal VH genes (13–16). "
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    ABSTRACT: In developing B cells, the immunoglobulin heavy chain (IgH) locus is thought to move from repressive to permissive chromatin compartments to facilitate its scheduled rearrangement. In mature B cells, maintenance of allelic exclusion has been proposed to involve recruitment of the non-productive IgH allele to pericentromeric heterochromatin. Here, we used an allele-specific chromosome conformation capture combined with sequencing (4C-seq) approach to unambigously follow the individual IgH alleles in mature B lymphocytes. Despite their physical and functional difference, productive and non-productive IgH alleles in B cells and unrearranged IgH alleles in T cells share many chromosomal contacts and largely reside in active chromatin. In brain, however, the locus resides in a different repressive environment. We conclude that IgH adopts a lymphoid-specific nuclear location that is, however, unrelated to maintenance of allelic exclusion. We additionally find that in mature B cells—but not in T cells—the distal VH regions of both IgH alleles position themselves away from active chromatin. This, we speculate, may help to restrict enhancer activity to the productively rearranged VH promoter element.
    Nucleic Acids Research 06/2013; 41(14). DOI:10.1093/nar/gkt491 · 9.11 Impact Factor
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    • "The antigen-receptor loci have afforded a rich model for studying the epigenetic mechanisms underlying regulation of programmed recombination in developing lymphocytes. It has been shown that intralocus loop formation (locus contraction), changes in chromatin landscape, and dynamic association of antigen-receptor loci with repressive pericentromeric heterochromatin (PCH) contribute (Chaumeil and Skok, 2012; Hewitt et al., 2010). However, we do not know how higher-order nuclear organization of antigen receptor loci is integrated with these various aspects of regulation and what role it plays in controlling this complex process in individual cells. "
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    ABSTRACT: V(D)J recombination is essential for generating a diverse array of B and T cell receptors that can recognize and combat foreign antigens. As with any recombination event, tight control is essential to prevent the occurrence of genetic anomalies that drive cellular transformation. One important aspect of regulation is directed targeting of the RAG recombinase. Indeed, RAG accumulates at the 3' end of individual antigen receptor loci poised for rearrangement; however, it is not known whether focal binding is involved in regulating cleavage, and what mechanisms lead to enrichment of RAG in this region. Here, we show that monoallelic looping out of the 3' end of the T cell receptor α (Tcra) locus, coupled with transcription and increased chromatin/nuclear accessibility, is linked to focal RAG binding and ATM-mediated regulation of monoallelic cleavage on looped-out 3' regions. Our data identify higher-order loop formation as a key determinant of directed RAG targeting and the maintenance of genome stability.
    Cell Reports 02/2013; 3(2):359-70. DOI:10.1016/j.celrep.2013.01.024 · 8.36 Impact Factor
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