Distinct Control of the Frequency and Allelic Exclusion of the Vβ Gene Rearrangement at the TCRβ Locus

Sieh, Ping; Chen, Jianzhu

doi:10.4049/jimmunol.167.4.2121

Cited by 19 publications

(18 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, targeting of a V gene into the V-D intergenic region of the Tcr␤ locus, 7 kb upstream of D ␤ J ␤ , failed to increase its recombination frequency (62), whereas removal of the entire V-D region did (63). In the former study, it was concluded that the flanking sequences controlled V recombination frequency, independent of its location.…”

Section: Discussionmentioning

confidence: 89%

The Mouse Immunoglobulin Heavy Chain V-D Intergenic Sequence Contains Insulators That May Regulate Ordered V(D)J Recombination

Featherstone¹,

Wood²,

Bowen³

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

V(D)J recombination of the multigene antigen receptor loci is essential for the generation of a diverse antigen receptor repertoire. Recombination is strictly regulated, occurring only in lymphocytes due to restricted expression of the recombination activating gene enzymes, RAG1 and RAG2, therein. Further, T cell receptors only recombine in T cells, B cell receptors only recombine in B cells, and the loci only recombine at specific stages in lymphocyte differentiation. In B cells, the Igh recombines before the Ig light chains. Finally some antigen receptor loci (e.g. the Igh) have two ordered recombination events. A D gene first recombines with a J gene on both alleles, followed by recombination of a V gene to the DJ recombined segment. Once a productive VDJ rearrangement has been generated, further V to DJ recombination is prevented on the second allele, a process termed allelic exclusion, which in B cells ensures that each B cell expresses a monoclonal IgH (1).Ordered recombination is crucial for antigen receptor integrity, but key questions remain: how is recombination order achieved, and how is it regulated? Numerous studies have suggested that order is achieved through alterations in the chromatin conformation of individual gene domains at sequential stages of lymphocyte development (2). In the mouse Igh locus, the D-J-C region acquires histone post-translational modifications characteristic of open chromatin before the V region (3, 4). Non-coding RNA transcripts, including I, generated from E, located 3Ј of the J genes (5), and o, transcribed from the promoter of the most 3Ј D gene, DQ52, occur on germ line alleles (6). Following D to J recombination, non-coding transcripts are generated from the V genes (7,8). Furthermore, extensive antisense intergenic transcription occurs throughout the D and J domains before D to J, and then throughout the V domain before V to DJ recombination (9, 10). Nuclear positioning may also play a role in ordered V(D)J recombination. The Igh locus is tethered at the nuclear periphery via the V region in non-B cells (11,12). Relocation toward euchromatic regions occurs preferentially from the DJC end, favoring D to J recombination. Furthermore, locus compaction through DNA looping is required for distal V gene recombination (13,14). Several transcription factors, including Pax5 (13), YY1 (15), and Ikaros (16), play a role in looping, and in their absence, only the D-proximal V genes recombine. Following productive V(D)J recombination and cell surface expression of an IgH polypeptide, several of the above processes are reversed to silence V to DJ recombination of the second allele by allelic exclusion. Both Igh V regions decontract, V region germ line transcription is lost, and the second Igh allele is recruited to pericentric heterochromatin via the D-distal V genes (1). In contrast, both DJC regions remain transcriptionally active (9, 17). Thus, there is differential chromatin regulation of both activation and inactivation of the DJC versus V regions of the Igh locus.

show abstract

Section: Discussionmentioning

confidence: 89%

The Mouse Immunoglobulin Heavy Chain V-D Intergenic Sequence Contains Insulators That May Regulate Ordered V(D)J Recombination

Featherstone¹,

Wood²,

Bowen³

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…However, very limited studies have addressed the effects of such a large intron on recombination and accesibility of the TCR␤ locus. Recently, Sieh et al (17) showed that a certain V␤ gene is not strikingly altered in its recombination frequency when it was inserted 6.8 kb upstream of the D␤1-J␤1 cluster, which was estimated to be outside of the E␤ regulatory region. Using recombination activating gene (RAG)2 Ϫ/Ϫ mice, Chen et al (18) showed that expression of the V␤ germline transcription before rearrangement does not correlate with proximity to E␤ enhancer.…”

Section: Uring Early Development Of ␣␤ T Cells the Tcr␤ Gene Is Rementioning

confidence: 99%

Increase of TCR Vβ Accessibility within Eβ Regulatory Region Influences its Recombination Frequency But Not Allelic Exclusion

Senoo

Wang

Suzuki

et al. 2003

The Journal of Immunology

View full text Add to dashboard Cite

Seventy percent of the murine TCRβ locus (475 kb) was deleted to generate a large deleted TCRβ (βLD) allele to investigate a possible linkage between germline transcription, recombination frequency, and allelic exclusion of the TCR Vβ genes. In these βLD/LD mice, the TCRβ gene locus contained only four Vβ genes at the 5′ side of the locus, and consequently, the Vβ10 gene was located in the original Dβ1-Jβ1cluster within the Eβ regulatory region. We showed that the frequency of recombination and expression of the Vβ genes are strongly biased to Vβ10 in these mutant mice even though the proximity of the other three 5′Vβ genes was also greatly shortened toward the Dβ-Jβ cluster and the Eβ enhancer. Accordingly, the germline transcription of the Vβ10 gene in βLD/LD mice was exceptionally enhanced in immature double negative thymocytes compared with that in wild-type mice. During double negative-to-double positive transition of thymocytes, the level of Vβ10 germline transcription was prominently increased in βLD/LD recombination activating gene 2-deficient mice receiving anti-CD3ε Ab in vivo. Interestingly, however, despite the increased accessibility of the Vβ10 gene in terms of transcription, allelic exclusion of this Vβ gene was strictly maintained in βLD/LD mice. These results provide strong evidence that increase of Vβ accessibility influences frequency but not allelic exclusion of the TCR Vβ rearrangement if the Vβ gene is located in the Eβ regulatory region.

show abstract

“…While the putative global regulator might have contributed to the residual V␤13 accessibility and rearrangement observed in P13 Ϫ/Ϫ mice, our results strongly suggest that the individual promoter also plays a critical role in targeting specific V␤ gene for rearrangement. Previously, our investigators have shown that when the V␤13 gene segment together with the promoter were inserted upstream of the D␤1 gene segment, the inserted V␤13 gene segment rearranged at the same frequency as the natural copy (29). Together, these findings strongly suggest that the variable gene promoter plays an essential role in regulating local access of gene segments for rearrangement.…”

Section: Discussionmentioning

confidence: 54%

“…However, cis elements that mediate allelic exclusion are not known. When the V␤13 gene segment together with the promoter were inserted upstream of the D␤1 gene segment, the inserted V␤13 gene segment continued to rearrange in the presence of a TCR transgene expression (29), indicating that the promoter alone is not sufficient to mediate allelic exclusion.…”

Section: Discussionmentioning

confidence: 99%

“…In CD4 ϩ CD8 ϩ (DP) thymocytes, where TCR␤ allelic exclusion is in effect, V␤ transcription, nuclease sensitivity, and association with acetylated histones are markedly reduced. When a V␤ gene segment together with 3.6-kb 5Ј sequences, encompassing the promoter, were inserted 6.8 kb upstream of the D␤1 gene segment, the inserted V␤ gene segment rearranged at the same frequency as the natural copy but was no longer subject to allelic exclusion control (29), indicating distinct controls of the frequency and allelic exclusion of V␤ gene rearrangement. However, beyond these preliminary observations, little is known about the specific cis elements that modulate variable gene accessibility for rearrangement initially and then for allelic exclusion.…”

Section: Cd8mentioning

confidence: 99%

See 1 more Smart Citation

The T-Cell Receptor β Variable Gene Promoter Is Required for Efficient Vβ Rearrangement but Not Allelic Exclusion

Ryu

Haines

Lee

et al. 2004

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

To investigate the role of promoters in regulating variable gene rearrangement and allelic exclusion, we constructed mutant mice in which a 1.2-kb region of the V␤13 promoter was either deleted (P13 ؊/؊ ) or replaced with the simian virus 40 minimal promoter plus five copies of Gal4 DNA sequences (P13 R/R ). In P13 ؊/؊ mice, cleavage, rearrangement, and transcription of V␤13, but not the flanking V␤ gene segments, were significantly inhibited. In P13 R/R mice, inhibition of V␤13 rearrangement was less severe and was not associated with any apparent reduction in V␤13 cleavage. Expression of a T-cell receptor (TCR) transgene blocked cleavages at the normal V␤13-recombination signal sequence junction and V␤13 coding joint formation of both wild-type and mutant V␤13 alleles. However, a low level of aberrant V␤13 cleavage was consistently detected, especially in TCR transgenic P13 R/R mice. These findings suggest that the variable gene promoter is required for promoting local recombination accessibility of the associated V␤ gene segment. Although the promoter is dispensable for allelic exclusion, it appears to suppress aberrant V␤ cleavages during allelic exclusion.The variable regions of immunoglobulin (Ig) and T cell receptor (TCR) genes are assembled from variable (V), diversity (D), and joining (J) gene segments. V(D)J recombination is tightly regulated in the context of lymphocyte development, exhibiting lineage, developmental stage, and allele specificity (1,13,24,32). Although recombination at different TCR and Ig loci is mediated by the same recombinase complex and conserved recombination signal sequences (RSS), complete rearrangements of TCR genes are limited to T cells, while complete rearrangements of Ig genes are limited to B cells. Within the appropriate cell lineage, recombination is regulated temporally and in a stage-specific manner. In addition, in a given lymphocyte, only one of two alleles of antigen receptor loci usually undergoes functional rearrangement, a process known as allelic exclusion.Studies have shown that transcriptional regulatory elements, such as promoters and enhancers, play an important role in targeting specific gene segments for recombination. Deletion of the enhancer at any of the TCR␤, TCR␦, TCR␣, IgH, and Ig loci results in a severe reduction in the level of rearrangement at the respective loci (4,5,7,11,14,27,31,41,42). Similarly, deletion of the PD␤1 promoter immediately upstream of the D␤1 gene segment at the TCR␤ locus significantly impairs D␤1 rearrangement (40, 41). To date, most evidence suggests that enhancers and promoters regulate V(D)J recombination by modulating chromatin structures and rendering gene segments accessible to RAG cleavage (13,24,32).Among the various levels of control, the most complex regulation is probably allelic exclusion. Like lineage-and stagespecific regulations, allelic exclusion is apparently also achieved through modulating access of gene segments to RAG cleavage (13,15,24,32). For example, TCR␤ allelic exclusion is regulated at the V␤-to-D...

show abstract

Distinct Control of the Frequency and Allelic Exclusion of the Vβ Gene Rearrangement at the TCRβ Locus

Cited by 19 publications

References 54 publications

The Mouse Immunoglobulin Heavy Chain V-D Intergenic Sequence Contains Insulators That May Regulate Ordered V(D)J Recombination

The Mouse Immunoglobulin Heavy Chain V-D Intergenic Sequence Contains Insulators That May Regulate Ordered V(D)J Recombination

Increase of TCR Vβ Accessibility within Eβ Regulatory Region Influences its Recombination Frequency But Not Allelic Exclusion

The T-Cell Receptor β Variable Gene Promoter Is Required for Efficient Vβ Rearrangement but Not Allelic Exclusion

Contact Info

Product

Resources

About