Developmental Stage-Specific Regulation of TCR-α-Chain Gene Assembly by Intrinsic Features of the TEA Promoter

Huang, Ching-Yu; Sleckman, Barry P.

doi:10.4049/jimmunol.179.1.449

Cited by 7 publications

(5 citation statements)

References 28 publications

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“…However as noted previously, the abundance of H3K4me2 can be difficult to interpret. Reduced transcription at TRDV5 was consistent with previous data (18); however, we did not detect differences in H3ac, H4ac or H3K4me2 at this site on E δ -deficient alleles. Nevertheless, although H3K4me3 at TRDV5 was very low on wild-type alleles, it was still 5–10-fold over the IgG control in different experiments (data not shown), and, consistent with the transcription data, averaged 8.5-fold over E δ −/− alleles (Fig.…”

Section: Resultssupporting

confidence: 93%

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Long-Distance Regulation of Fetal Vδ Gene Segment TRDV4 by the Tcrd Enhancer

Hao

Krangel

2011

The Journal of Immunology

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Murine Tcra and Tcrd gene segments are organized into single genetic locus (Tcra/Tcrd locus) which undergoes V(D)J recombination in CD4−CD8− double negative (DN) thymocytes to assemble Tcrd genes and in CD4+CD8+ double positive (DP) thymocytes to assemble Tcra genes. Recombination events are regulated by two developmental stage-specific enhancers, Eδ and Eα. Effects of Eα on Trca/Tcrd locus chromatin have been well documented, but effects of Eδ have not. In this regard, Eα acts over long distances to activate many Vα and Jα segments for recombination in DP thymocytes. However, in DN thymocytes it is unclear whether Eδ functions over long distances to regulate Vδ gene segments, or only functions locally to regulate Dδ and Jδ gene segments. Here we analyzed germline transcription, histone modifications and recombination on wild-type and Eδ-deficient alleles in adult and fetal thymocytes. We found that Eδ functions as a local enhancer whose influence is limited to no more than about 10 kb in either direction (including Dδ, Jδ and TRDV5 gene segments) in adult DN thymocytes. However we identified a unique long-distance role for Eδ promoting accessibility and recombination of fetal Vδ gene segment TRDV4, over a distance of 55 kb, in fetal thymocytes. TRDV4 recombination is specifically repressed in adult thymocytes. We found that this repression is enforced by a developmentally regulated loss of histone acetylation. Constitutively high levels of a suppressive modification, histone H3 lysine 9 dimethylation, may contribute to repression as well.

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Section: Resultssupporting

confidence: 93%

“…Although germline transcription of TRDV5, located 10 kb downstream of E δ , was found to be reduced on E δ -deficient alleles (18), information about more distant V δ gene segments has been lacking. Furthermore, no information is available regarding the chromatin modification profile of E δ -deficient alleles.…”

Section: Introductionmentioning

confidence: 99%

Long-Distance Regulation of Fetal Vδ Gene Segment TRDV4 by the Tcrd Enhancer

Hao

Krangel

2011

The Journal of Immunology

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“…Junctions from TCRα SJ mice were amplified using the indicated primers (Supplementary Table 4). TCR Jα usage was determined as previously described 29 .…”

Section: Methodsmentioning

confidence: 99%

53BP1 facilitates long-range DNA end-joining during V(D)J recombination

Difilippantonio

Gapud

Wong

et al. 2008

Nature

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276

287

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V(D)J recombination and class switch recombination employ overlapping but distinct non-homologous end-joining (NHEJ) pathways to repair DNA double strand break (DSB) intermediates. 53BP1 is a DNA damage response protein that is rapidly recruited to sites of chromosomal DSBs, where it appears to function in a subset of ataxia-telangiectasia mutated (ATM) kinase, H2AX- and MDC1- dependent events1,2. A 53BP1 dependent end joining pathway has been described that is dispensable for V(D)J recombination but essential for class-switch recombination CSR3, 4. Here, we report a previously unrecognized defect in the joining phase of V(D)J recombination in 53BP1 deficient lymphocytes distinct from that found in classical NHEJ-, H2AX-, MDC1- and Atm-deficient mice. Absence of 53BP1 leads to impairment of distal V-DJ joining with extensive degradation of un-repaired coding ends and episomal signal joint reintegration at V(D)J junctions. This results in apoptosis, loss of T-cell receptor alpha locus integrity and lymphopenia. Further impairment of the apoptotic checkpoint causes propagation of lymphocytes bearing antigen receptor breaks. These data suggest a more general role for 53BP1 in maintaining genomic stability during long range joining of DNA breaks.

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“…As in the TCRγ locus, rearrangement of Trdv to Trdd ‐ Trdv brings the Trdv promoters in closer proximity to Eδ , increasing expression. Just downstream of Eδ is the T early activation ( TEA ) promoter, which drives germline expression of the Traj segments (Huang & Sleckman, 2007). Finally, there is a TCRα enhancer ( Eα ) downstream of the Trac exon, at the 3′ end of the TCRα/δ locus.…”

Section: Transcriptional Control Of the Tcr Locimentioning

confidence: 99%

Direct regulation of TCR rearrangement and expression by E proteins during early T cell development

Anderson

Rocha

2022

WIREs Mechanisms of Disease

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γδ T cells are widely distributed throughout mucosal and epithelial cell‐rich tissues and are an important early source of IL‐17 in response to several pathogens. Like αβ T cells, γδ T cells undergo a stepwise process of development in the thymus that requires recombination of genome‐encoded segments to assemble mature T cell receptor (TCR) genes. This process is tightly controlled on multiple levels to enable TCR segment assembly while preventing the genomic instability inherent in the double‐stranded DNA breaks that occur during this process. Each TCR locus has unique aspects in its structure and requirements, with different types of regulation before and after the αβ/γδ T cell fate choice. It has been known that Runx and Myb are critical transcriptional regulators of TCRγ and TCRδ expression, but the roles of E proteins in TCRγ and TCRδ regulation have been less well explored. Multiple lines of evidence show that E proteins are involved in TCR expression at many different levels, including the regulation of Rag recombinase gene expression and protein stability, induction of germline V segment expression, chromatin remodeling, and restriction of the fetal and adult γδTCR repertoires. Importantly, E proteins interact directly with the cis‐regulatory elements of the TCRγ and TCRδ loci, controlling the predisposition of a cell to become an αβ T cell or a γδ T cell, even before the lineage‐dictating TCR signaling events. This article is categorized under: Immune System Diseases > Stem Cells and Development Immune System Diseases > Genetics/Genomics/Epigenetics

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Developmental Stage-Specific Regulation of TCR-α-Chain Gene Assembly by Intrinsic Features of the TEA Promoter

Cited by 7 publications

References 28 publications

Long-Distance Regulation of Fetal Vδ Gene Segment TRDV4 by the Tcrd Enhancer

Long-Distance Regulation of Fetal Vδ Gene Segment TRDV4 by the Tcrd Enhancer

53BP1 facilitates long-range DNA end-joining during V(D)J recombination

Direct regulation of TCR rearrangement and expression by E proteins during early T cell development

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