Preparing Targets for V(D)J Recombinase: Transcription Paves the Way

Sleckman, Barry P.; Oltz, Eugene M.

doi:10.4049/jimmunol.1103195

Cited by 10 publications

(8 citation statements)

References 29 publications

(21 reference statements)

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“…Lineage, stage, order, and feedback regulation of V(D)J recombination are mediated “epigenetically” by modulating “accessibility” of particular loci or regions of loci to RAG (Sleckman and Oltz, 2012). Mouse IgH contains several hundred V H s, 13 Ds and four J H s in an approximately 3-Mb region upstream of the C H s (Figure 2B; Figure 3).…”

Section: Mechanism and Control Of V(d)j Recombinationmentioning

confidence: 99%

“…In this regard, the J H to Cμ intronic enhancer (“iEμ”) is required for V H to DJ H joining, but not D to J H joining, which relies on undefined accessibility elements (Subrahmanyam and Sen, 2012). Transcription of unrearranged (“germline”) V H s in pro-B cells that is down-regulated in more mature stages was the first accessibility correlate for V(D)J recombination (Sleckman and Oltz, 2012). Widespread antisense transcription also occurs throughout the V H locus (Matheson and Corcoran, 2012).…”

Section: Mechanism and Control Of V(d)j Recombinationmentioning

confidence: 99%

See 1 more Smart Citation

Mechanisms of Programmed DNA Lesions and Genomic Instability in the Immune System

Alt¹,

Zhang²,

Meng³

et al. 2013

Cell

423

626

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Chromosomal translocations involving antigen receptor loci are common in lymphoid malignancies. Translocations require DNA double-strand breaks (DSBs) at two chromosomal sites, their physical juxtaposition, and their fusion by end joining. Ability of lymphocytes to generate diverse repertoires of antigen receptors and effector antibodies derives from programmed genomic alterations that produce DSBs. We discuss these lymphocyte-specific processes, with a focus on mechanisms that provide requisite DSB target specificity and mechanisms that suppress DSB translocation. We also discuss recent work that provides new insights into DSB repair pathways and influences of three-dimensional genome organization on physiological processes and cancer genomes.

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Section: Mechanism and Control Of V(d)j Recombinationmentioning

confidence: 99%

Section: Mechanism and Control Of V(d)j Recombinationmentioning

confidence: 99%

Mechanisms of Programmed DNA Lesions and Genomic Instability in the Immune System

Alt¹,

Zhang²,

Meng³

et al. 2013

Cell

423

626

View full text Add to dashboard Cite

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“…A second set of enhancers within the Igh 3′ regulatory region (3′ Igh RR) lies ∼200 kb downstream, just beyond the last set of C H exons (5). V(D)J recombination at Igh is regulated on multiple levels, in each case by modulating the accessibility of the substrate Vs, Ds, and Js and their flanking RSSs to RAG cleavage (6,7). In this regard, Igh V(D)J recombination events are ordered and are stage specific; D-to-J H joining occurs first, usually on both alleles, in preprogenitor B cells, followed by the joining of a V H to a preassembled DJ H complex in progenitor B (pro-B) cells (8,9).…”

mentioning

confidence: 99%

CTCF-binding elements 1 and 2 in the Igh intergenic control region cooperatively regulate V(D)J recombination

Lin

Guo²,

Su³

et al. 2015

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

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Ig heavy chain (IgH) variable region exons are assembled from V, D, and J gene segments during early B-lymphocyte differentiation. A several megabase region at the "distal" end of the mouse IgH locus (Igh) contains hundreds of V H s, separated by an intergenic region from Igh Ds, J H s, and constant region exons. Diverse primary Igh repertoires are generated by joining Vs, Ds, and Js in different combinations, with a given B cell productively assembling only one combination. The intergenic control region 1 (IGCR1) in the V H -to-D intergenic region regulates Igh V(D)J recombination in the contexts of developmental order, lineage specificity, and feedback from productive rearrangements. IGCR1 also diversifies IgH repertoires by balancing proximal and distal V H use. IGCR1 functions in all these regulatory contexts by suppressing predominant rearrangement of D-proximal V H s. Such IGCR1 functions were neutralized by simultaneous mutation of two CCCTC-binding factor (CTCF)-binding elements (CBE1 and CBE2) within it. However, it was unknown whether only one CBE mediates IGCR1 functions or whether both function in this context. To address these questions, we generated mice in which either IGCR1 CBE1 or CBE2 was replaced with scrambled sequences that do not bind CTCF. We found that inactivation of CBE1 or CBE2 individually led to only partial impairment of various IGCR1 functions relative to the far greater effects of inactivating both binding elements simultaneously, demonstrating that they function cooperatively to achieve full IGCR1 regulatory activity. Based on these and other findings, we propose an orientation-specific looping model for synergistic CBE1 and CBE2 functions. Recombination activating genes 1 and 3 (RAG1 and RAG2) comprise the lymphocyte-specific endonuclease ("RAG") that initiates V(D)J recombination by generating DNA double-strand breaks at recombination signal sequences (RSSs) adjacent to participating Vs, Ds, and Js (2). Subsequently, RAG-cleaved segments are joined by classical nonhomologous end-joining (3).In B cells, V(D)J exons are assembled within the IgH locus (Igh) and within either of two Igl loci (Igκ or Igλ). The murine Igh spans 3 Mb on chromosome 12 (Fig. 1). Approximately 150 V H s are scattered within a 2.7-Mb upstream portion of Igh, followed by a 100-kb intergenic region that separates the most downstream V H (V H 81X) from the first of 13 Ds (4). Four J H s lie downstream of the Ds and are separated from the first of eight sets of IgH constant region exons by a several-kilobase region that harbors the intronic Igh enhancer (iEμ). A second set of enhancers within the Igh 3′ regulatory region (3′ Igh RR) lies ∼200 kb downstream, just beyond the last set of C H exons (5). V(D)J recombination at Igh is regulated on multiple levels, in each case by modulating the accessibility of the substrate Vs, Ds, and Js and their flanking RSSs to RAG cleavage (6, 7). In this regard, Igh V(D)J recombination events are ordered and are stage specific; D-to-J H joining occurs first, usually on both ...

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“…In developing B-lineage cells, accessibility to the major remodeling events [VDJ recombination, somatic hypermutation (SHM), class switch recombination (CSR), and locus suicide recombination] depends on epigenetic changes and germ-line transcription of many regions, including V H promoters, I/switch region promoters, cis-regulatory region enhancers, and chromatin insulators (1)(2)(3). A focus on knockout (KO) models for IgH cis-regulatory regions (enhancers and chromatin insulators) is a means to simplify the regulation picture.…”

mentioning

confidence: 99%

Sequential activation and distinct functions for distal and proximal modules within the IgH 3′ regulatory region

Garot

Marquet

Saintamand

et al. 2016

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

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As a master regulator of functional Ig heavy chain (IgH) expression, the IgH 3′ regulatory region (3′RR) controls multiple transcription events at various stages of B-cell ontogeny, from newly formed B cells until the ultimate plasma cell stage. The IgH 3′RR plays a pivotal role in early B-cell receptor expression, germ-line transcription preceding class switch recombination, interactions between targeted switch (S) regions, variable region transcription before somatic hypermutation, and antibody heavy chain production, but the functional ranking of its different elements is still inaccurate, especially that of its evolutionarily conserved quasipalindromic structure. By comparing relevant previous knockout (KO) mouse models (3′RR KO and hs3b-4 KO) to a novel mutant devoid of the 3′RR quasi-palindromic region (3′PAL KO), we pinpointed common features and differences that specify two distinct regulatory entities acting sequentially during B-cell ontogeny. Independently of exogenous antigens, the 3′RR distal part, including hs4, fine-tuned B-cell receptor expression in newly formed and naïve B-cell subsets. At mature stages, the 3′RR portion including the quasi-palindrome dictated antigen-dependent locus remodeling (global somatic hypermutation and class switch recombination to major isotypes) in activated B cells and antibody production in plasma cells.immunoglobulin gene regulation | enhancers | B-cell development I mmunoglobulin heavy chain (IgH) expression is critical for B-cell development and survival. In developing B-lineage cells, accessibility to the major remodeling events [VDJ recombination, somatic hypermutation (SHM), class switch recombination (CSR), and locus suicide recombination] depends on epigenetic changes and germ-line transcription of many regions, including V H promoters, I/switch region promoters, cis-regulatory region enhancers, and chromatin insulators (1-3). A focus on knockout (KO) models for IgH cis-regulatory regions (enhancers and chromatin insulators) is a means to simplify the regulation picture. At the preproB stage, the IgH locus undergoes long-range looping in a "rosette-like" structure that brings into close proximity major IgH regulatory regions, such as the V H to D H intergenic control regions (IGCR1 and -2), the Eμ intronic enhancer, the 3′ regulatory region (3′RR), and the 3′IgH CTCF-binding elements (CBEs) (4-6). Initiation of VDJ recombination is assisted by the Eμ enhancer, which provides efficient transcription and accessibility to initiate D H to J H rearrangements (7-10), as well as the IGCR1 and -2 elements that ordinate the V H to DJ H second recombination step (5, 11-13). Devoid of enhancer activity (14, 15), 3′CBE (hs5 to hs8) likely participate in IgH folding before VDJ recombination because deletion of hs5 to -7 only impacts use of proximal V H regions (16). In pre-B cells, once a functional H chain is expressed as a component of the pre-B-cell recptor (BCR), the Eμ enhancer function switches from DJ H region accessibility to Igμ chain expression, and consequent...

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Preparing Targets for V(D)J Recombinase: Transcription Paves the Way

Cited by 10 publications

References 29 publications

Mechanisms of Programmed DNA Lesions and Genomic Instability in the Immune System

Mechanisms of Programmed DNA Lesions and Genomic Instability in the Immune System

CTCF-binding elements 1 and 2 in the Igh intergenic control region cooperatively regulate V(D)J recombination

Sequential activation and distinct functions for distal and proximal modules within the IgH 3′ regulatory region

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