A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation

Seitan, Vlad C.; Hao, Bingtao; Tachibana-Konwalski, Kikuë; Lavagnolli, Thais; Mira-Bontenbal, Hegias; Brown, Karen E.; Teng, Grace; Carroll, Tom; Terry, Anna; Horan, Katie; Marks, Hendrik; Adams, David J.; Schatz, David G.; Aragón, Luís; Fisher, Amanda G.; Krangel, Michael S.; Nasmyth, Kim; Merkenschlager, Matthias

doi:10.1038/nature10312

Cited by 223 publications

(286 citation statements)

References 39 publications

Supporting

Mentioning

266

Contrasting

Order By: Relevance

“…In conditional CTCF knockout mice, V gene usage in the Igk light chain locus was found to be altered, with increased recombination with proximal and reduced recombination with distal V segments. This was accompanied by corresponding changes in germline transcription at these locations, suggesting that CTCF, such as cohesin [47], mediates gene usage of the antigen receptor loci via the local regulation of germline transcription [66]. In this model, germline transcription increases accessibility of the region, which facilitates their selection for recombination [67].…”

Section: Ctcf Function At Individual Gene Locimentioning

confidence: 99%

“…Also at the b-globin locus cohesin has been implicated in chromatin looping, not only between the flanking CTCF sites but also between the LCR enhancer region and the downstream b-globin target genes [46]. Conditional deletion of cohesin in thymocytes was shown to disrupt the formation [47]. Pairwise comparison between two cell types revealed that it is mostly the CTCF-independent cohesin-binding events that show cell-type specificity.…”

Section: Ctcf and Cohesin Share Dna Binding Sitesmentioning

confidence: 99%

See 1 more Smart Citation

CTCF: the protein, the binding partners, the binding sites and their chromatin loops

Holwerda

Laat

2013

Phil. Trans. R. Soc. B

205

170

View full text Add to dashboard Cite

CTCF has it all. The transcription factor binds to tens of thousands of genomic sites, some tissue-specific, others ultra-conserved. It can act as a transcriptional activator, repressor and insulator, and it can pause transcription. CTCF binds at chromatin domain boundaries, at enhancers and gene promoters, and inside gene bodies. It can attract many other transcription factors to chromatin, including tissue-specific transcriptional activators, repressors, cohesin and RNA polymerase II, and it forms chromatin loops. Yet, or perhaps therefore, CTCF's exact function at a given genomic site is unpredictable. It appears to be determined by the associated transcription factors, by the location of the binding site relative to the transcriptional start site of a gene, and by the site's engagement in chromatin loops with other CTCF-binding sites, enhancers or gene promoters. Here, we will discuss genome-wide features of CTCF binding events, as well as locus-specific functions of this remarkable transcription factor.

show abstract

Section: Ctcf Function At Individual Gene Locimentioning

confidence: 99%

Section: Ctcf and Cohesin Share Dna Binding Sitesmentioning

confidence: 99%

CTCF: the protein, the binding partners, the binding sites and their chromatin loops

Holwerda

Laat

2013

Phil. Trans. R. Soc. B

205

170

View full text Add to dashboard Cite

show abstract

“…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.

View full text Add to dashboard Cite

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...

show abstract

“…It now is appreciated that cohesin has additional roles in nondividing cells, mediated in part by its ability to interact physically and functionally with CTCF at many genomic sites (32)(33)(34). Notably, cohesin was found to bind to E α and the TEAp and to facilitate their long-distance interaction in DP thymocytes (30). Thus, cohesin appears to regulate Tcra recombination by promoting contacts between cis-regulatory elements that are needed to generate accessible J α RSSs.…”

mentioning

confidence: 99%

“…1A). Recent work revealed that V α -to-J α recombination is compromised in mice that are conditionally deficient in cohesin (30). Cohesin is known to regulate sister chromatid segregation during mitosis (31).…”

mentioning

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.

Self Cite

153

View full text Add to dashboard Cite

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...

show abstract

A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation

Cited by 223 publications

References 39 publications

CTCF: the protein, the binding partners, the binding sites and their chromatin loops

CTCF: the protein, the binding partners, the binding sites and their chromatin loops

Unifying model for molecular determinants of the preselection Vβ repertoire

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

Contact Info

Product

Resources

About