CTCF-binding elements mediate control of V(D)J recombination

Guo, Chunguang; Yoon, Hye Suk; Franklin, Andrew; Jain, Suvi; Ebert, Anja; Cheng, Hwei-Ling; Hansen, Erica; Despo, Orion; Bossen, Claudia; Vettermann, Christian; Bates, Jamie; Richards, Nicholas; Myers, David E.; Patel, Harin; Gallagher, M. J.; Schlissel, Mark S.; Murre, Cornelis; Busslinger, Meinrad; Giallourakis, Cosmas; Alt, Frederick W.

doi:10.1038/nature10495

Cited by 248 publications

(383 citation statements)

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“…Although not directly related to the control of gene expression, the case of the Igh locus provides another interesting example of interactions between noncoding elements (Guo et al, 2011). This genomic region contains multiple CTCF insulator elements whose interactions are necessary to produce correct V(D)J rearrangements (Guo et al, 2011).…”

Section: Interactions Between Regulatory Elementsmentioning

confidence: 99%

Multiple layers of complexity in cis‐regulatory regions of developmental genes

Frankel

2012

Developmental Dynamics

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Genomes contain the necessary information to ensure that genes are expressed in the right place, at the right time, and with the proper rate. Metazoan developmental genes often possess long stretches of DNA flanking their coding sequences and/or large introns which contain elements that influence gene expression. Most of these regulatory elements are relatively small and can be studied in isolation. For example, transcriptional enhancers, the elements that generate the expression pattern of a gene, have been traditionally studied with reporter constructs in transgenic animals. These studies have provided and will provide invaluable insights into enhancer evolution and function. However, this experimental approach has its limits; often, enhancer elements do not faithfully recapitulate native expression patterns. This fact suggests that additional information in cis-regulatory regions modulates the activity of enhancers and other regulatory elements. Indeed, recent studies have revealed novel functional aspects at the level of whole cis-regulatory regions. First, the discovery of ''shadow enhancers.'' Second, the ubiquitous interactions between cis-regulatory elements. Third, the notion that some cis-regulatory regions may not function in a modular manner. Last, the effect of chromatin conformation on cis-regulatory activity. In this article, I describe these recent findings and discuss open questions in the field.

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Section: Interactions Between Regulatory Elementsmentioning

confidence: 99%

Multiple layers of complexity in cis‐regulatory regions of developmental genes

Frankel

2012

Developmental Dynamics

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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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“…19 Interestingly, it was demonstrated that cooperation between T-bet and Ctcf is required for Th1 cell-specific expression of IFN-c. 20 In addition, Ctcf also plays a role in the regulation of V(D)J recombination events and V gene usage at the Ig H and L chain loci in B cells. 21,22 The role of Ctcf in development and function of myeloid cells in vivo has not been investigated. Here, we used the transgenic Cre-loxP system to generate conditional myeloid-specific Ctcf-knockout mice, allowing analysis of the role of Ctcf in the development and function of macrophages in vivo and in vitro.…”

Section: Introductionmentioning

confidence: 99%