A Multifunctional Element in the Mouse <i>Igκ</i> Locus That Specifies Repertoire and <i>Ig</i> Loci Subnuclear Location

Xiang, Yougui; Zhou, Xiaorong; Hewitt, Susannah L.; Skok, Jane A.; Garrard, William T.

doi:10.4049/jimmunol.1003794

Cited by 59 publications

(92 citation statements)

References 65 publications

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“…At Igh and Igk, CTCF sites are generally intergenic except for those in the proximal one-third of the V H array, which are downstream of V H RSSs; moreover, CTCF sites are not associated with the major Igh and Igk enhancer elements (25,26,(48)(49)(50). At these loci, CTCF promotes long-distance interactions between CTCFbinding elements (24)(25)(26), but these looping interactions appear primarily to restrict or insulate the activities of the major enhancer elements.…”

Section: Discussionmentioning

confidence: 99%

“…At these loci, CTCF promotes long-distance interactions between CTCFbinding elements (24)(25)(26), but these looping interactions appear primarily to restrict or insulate the activities of the major enhancer elements. As examples, CTCF-binding regions situated between V H and D H J H and between V κ and J κ segments appear to block the enhancers from activating relatively proximal V segments, thus promoting the formation of Igh and Igk repertoires in which natural biases to proximal V segments are suppressed (24,26,50). Our data suggest that CTCF binding at the TEA promoter inhibits E α from activating Tcrd gene segments immediately upstream; thus, by analogy to Igh and Igk, the TEAp CTCF site Fig.…”

Section: Discussionmentioning

confidence: 99%

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Tcragene recombination is supported by aTcraenhancer- and CTCF-dependent chromatin hub

Shih

Verma-Gaur

Torkamani

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

153

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Antigen receptor locus V(D)J recombination requires interactions between widely separated variable (V), diversity (D), and joining (J) gene segments, but the mechanisms that generate these interactions are not well understood. Here we assessed mechanisms that direct developmental stage-specific long-distance interactions at the Tcra/Tcrd locus. The Tcra/Tcrd locus recombines Tcrd gene segments in CD4 − CD8 − double-negative thymocytes and Tcra gene segments in CD4 + CD8 + double-positive thymocytes. Initial V α -to-J α recombination occurs within a chromosomal domain that displays a contracted conformation in both thymocyte subsets. We used chromosome conformation capture to demonstrate that the Tcra enhancer (E α ) interacts directly with V α and J α gene segments distributed across this domain, specifically in double-positive thymocytes. Moreover, E α promotes interactions between these V α and J α segments that should facilitate their synapsis. We found that the CCCTC-binding factor (CTCF) binds to E α and to many locus promoters, biases E α to interact with these promoters, and is required for efficient V α -J α recombination. Our data indicate that E α and CTCF cooperate to create a developmentally regulated chromatin hub that supports V α -J α synapsis and recombination.T-cell development | T-cell receptor | thymus T and B cells produce diverse antigen receptors through the recombination of variable (V), diversity (D), and joining (J) gene segments at the T-cell receptor (Tcra, Tcrb, Tcrg, and Tcrd) and Ig (Igh, Igκ, and Igλ) loci. This V(D)J recombination is initiated by the lymphoid-specific recombination-activating gene-1 (RAG-1) and RAG-2 proteins, which recognize the recombination signal sequences (RSSs) that flank all V, D, and J gene segments and then cleave the DNA between the RSSs and the adjacent coding gene segments (1). A critical feature of the reaction is the assembly of a synaptic complex composed of two RSSs before the generation of RAG-dependent DNA doublestrand breaks (DSBs). As such, lineage-and developmental stagespecific V(D)J recombination events can be regulated not only by changes in RAG protein expression and RSS accessibility to RAG proteins but also by the ability of those RSSs to undergo synapsis (2).Conformational changes of antigen receptor loci are believed to support V(D)J recombination events because they can bring distant RSSs into proximity and therefore increase the probability of RSS synapsis (2, 3). Studies using 3D-FISH have demonstrated that lineage-and development stage-specific locus contraction marks the recombination windows at antigen receptor loci (3). For example, the 3-Mb Igh locus contracts specifically in pro-B cells to support V H -to-D H J H recombination (4-7). This contracted conformation brings distal and proximal V H segments, which are separated by megabases in the linear DNA sequence, to the vicinity of the D H J H cluster, presumably allowing all V H segments a similar opportunity for recombination (8). In addition, the mapping of Igh locus DNA-DNA...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tcragene recombination is supported by aTcraenhancer- and CTCF-dependent chromatin hub

Shih

Verma-Gaur

Torkamani

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

153

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“…Long-range interactions and locus conformations are determined in large part by CCCTC-binding factor (CTCF) and cohesin, factors that bind numerous sites throughout the mammalian genome forming loops containing the intervening DNA (16). With regard to AgR loci, deletion of CTCF, its binding sites, or essential cohesin subunits disrupt spatial interactions at Igk, Igh, and Tcra, respectively, and perturb V to (D)J recombination (17)(18)(19)(20).…”

Section: Significancementioning

confidence: 99%

Unifying model for molecular determinants of the preselection Vβ repertoire

Gopalakrishnan

Majumder

Predeus

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The primary antigen receptor repertoire is sculpted by the process of V(D)J recombination, which must strike a balance between diversification and favoring gene segments with specialized functions. The precise determinants of how often gene segments are chosen to complete variable region coding exons remain elusive. We quantified Vβ use in the preselection Tcrb repertoire and report relative contributions of 13 distinct features that may shape their recombination efficiencies, including transcription, chromatin environment, spatial proximity to their DβJβ targets, and predicted quality of recombination signal sequences (RSSs). We show that, in contrast to functional Vβ gene segments, all pseudo-Vβ segments are sequestered in transcriptionally silent chromatin, which effectively suppresses wasteful recombination. Importantly, computational analyses provide a unifying model, revealing a minimum set of five parameters that are predictive of Vβ use, dominated by chromatin modifications associated with transcription, but largely independent of precise spatial proximity to DβJβ clusters. This learned model-building strategy may be useful in predicting the relative contributions of epigenetic, spatial, and RSS features in shaping preselection V repertoires at other antigen receptor loci. Ultimately, such models may also predict how designed or naturally occurring alterations of these loci perturb the preselection use of variable gene segments.lymphocytes | T-cell receptor | gene regulation G ene activity is regulated at multiple levels to coordinate expression during development. At a most basic level, the collection of cis-acting elements for a genetic locus recruits transcription factors that alter its chromatin environment to either induce or repress gene activity. Emerging studies indicate that the 3D conformation of a locus also plays an important role in the regulation of its composite genes (1). At most genes, many levels of control are integrated to achieve the requisite gene expression state. For example, transcriptional promoters interact with their cognate enhancers over considerable distances in the linear genome to generate "hubs" where the two cis elements are in spatial proximity (1, 2).All of these regulatory strategies are used to generate functional Ig (Ig) and T-cell receptor (Tcr) genes during lymphocyte development (3). Each antigen receptor (AgR) locus is composed of multiple variable (V), joining (J), and sometimes diversity (D) gene segments that are assembled by the process of V (D)J recombination, creating a potential variable region exon (4). Recombination is mediated by the RAG-1/2 enzymatic complex, which is expressed in all developing lymphocytes and recognizes semiconserved recombination signal sequences (RSSs) flanking all AgR gene segments (5). On selection of two compatible gene segments by RAG-1/2, recombination proceeds via a DNA break/repair mechanism, ultimately fusing the two selected segments (4, 5).The assembly of AgR genes is strictly regulated despite a common collection of ge...

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“…59 Deletion of the SIS element resulted in decreased monoallelic Ig heterochromatin localization, reduced 0 germline transcription, and enhanced proximal V usage. 59,60 Next to strong CTCF binding at the 5Ј and 3Ј boundaries and the SIS element, 49 we identified approximately 60 CTCF-binding sites in the V region (in contrast to the previously reported low density of CTCF occupancy in the Ig locus 45 ). CTCF-binding sites were not evenly distributed over the Ig locus.…”

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confidence: 48%

DNA-binding factor CTCF and long-range gene interactions in V(D)J recombination and oncogene activation

Almeida¹,

Stadhouders

Thongjuea

et al. 2012

Blood

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Regulation of V(D)J recombination events at immunoglobulin (Ig) and T-cell receptor loci in lymphoid cells is complex and achieved via changes in substrate accessibility. Various studies over the last year have identified the DNA-binding zinc-finger protein CCCTC-binding factor (CTCF) as a crucial regulator of long-range chromatin interactions. CTCF often controls specific interactions by preventing inappropriate communication between neighboring regulatory elements or independent chromatin domains. Although recent gene targeting experiments demonstrated that the presence of the CTCF protein is not required for the process of V(D)J recombination per se, CTCF turned out to be essential to control order, lin-eage specificity and to balance the Ig V gene repertoire. Moreover, CTCF was shown to restrict activity of enhancer elements to the Ig locus. In this review, we discuss CTCF function in the regulation of V(D)J recombination on the basis of established knowledge on CTCF-mediated chromatin loop domains in various other loci, including the imprinted H19-Igf2 locus as well as the complex-globin, MHC class II and IFN-loci. Moreover, we discuss that loss of CTCF-mediated restriction of enhancer activity may well contribute to oncogenic activation , when in chromosomal transloca-tions Ig enhancer elements and onco-genes appear in a novel genomic context. (Blood. 2012;119(26):6209-6218)

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A Multifunctional Element in the Mouse Igκ Locus That Specifies Repertoire and Ig Loci Subnuclear Location

Cited by 59 publications

References 65 publications

Tcragene recombination is supported by aTcraenhancer- and CTCF-dependent chromatin hub

Tcragene recombination is supported by aTcraenhancer- and CTCF-dependent chromatin hub

Unifying model for molecular determinants of the preselection Vβ repertoire

DNA-binding factor CTCF and long-range gene interactions in V(D)J recombination and oncogene activation

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