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A discrete chromatin loop in the murine Tcra/Tcrd locus shapes the TCRδ and TCRα repertoires

ABSTRACT: The Tcra/Tcrd locus undergoes V(D)J recombination in CD4−CD8− double-negative (DN) thymocytes and CD4+CD8+ double-positive (DP) thymocytes to generate diverse TCRδ and TCRα repertoires, respectively. Here we reveal a Tcra/Tcrd locus chromatin interaction network in DN thymocytes that is formed by interactions between CTCF-binding elements (CBEs). Disruption of a discrete chromatin loop encompassing the Dδ, Jδ and Cδ gene segments allows a single Vδ segment to frequently contact and rearrange to Dδ and Jδ segments and dominate the adult TCRδ repertoire. Disruption of this loop also narrows the TCRα repertoire, which, we believe, follows as a consequence of the restricted TCRδ repertoire. Hence, a single CTCF-mediated chromatin loop directly regulates TCRδ diversity and indirectly regulates TCRα diversity. Examination of chromatin loops by 4C-seq from 4 viewpoints in two lymphoid cell compartments: CD4-CD8- thymocytes and naïve B splenocytes.

ORGANISM(S): Mus musculus

SUBMITTER: Zachary Carico

PROVIDER: E-GEOD-67442 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A discrete chromatin loop in the murine Tcra/Tcrd locus shapes the TCRδ and TCRα repertoires

Project description:The Tcra/Tcrd locus undergoes V(D)J recombination in CD4−CD8− double-negative (DN) thymocytes and CD4+CD8+ double-positive (DP) thymocytes to generate diverse TCRδ and TCRα repertoires, respectively. Here we reveal a Tcra/Tcrd locus chromatin interaction network in DN thymocytes that is formed by interactions between CTCF-binding elements (CBEs). Disruption of a discrete chromatin loop encompassing the Dδ, Jδ and Cδ gene segments allows a single Vδ segment to frequently contact and rearrange to Dδ and Jδ segments and dominate the adult TCRδ repertoire. Disruption of this loop also narrows the TCRα repertoire, which, we believe, follows as a consequence of the restricted TCRδ repertoire. Hence, a single CTCF-mediated chromatin loop directly regulates TCRδ diversity and indirectly regulates TCRα diversity.

2015-08-10 | GSE67442 | GEO

Tcrd rearrangement redirects a processive Tcra recombination program to expand the Tcra repertoire

Project description:The Tcra-Tcrd locus undergoes Tcrd rearrangement in DN thymocytes followed by primary and secondary Tcra rearrangements in DP thymocytes. Here we reveal the mechanisms underpinning combinatorial diversity in the Tcra repertoire. We show that V-alpha and J-alpha segments on individual Tcra alleles are used in stepwise and coordinated proximal-to-distal progressions during primary and secondary rearrangements, substantially constraining combinatorial diversity. Notably, Tcrd recombination in DN thymocytes diversifies the Tcra repertoire by truncating the V-alpha array to permit otherwise disfavored V-J combinations. Such diversification is important, because Trav1-Traj33+ mucosa-associated invariant T cells are depleted when Tcrd rearrangement is impaired. Our results reveal an important biological advantage conferred by the nested organization of Tcrd and Tcra gene segments.

2017-06-06 | GSE95826 | GEO

Trav15-dv6 family Tcrd rearrangements diversify the Tcra repertoire

Project description:Dauphars et al. show that prior Tcrd rearrangement is essential for a combinatorially diverse Tcra repertoire in mouse thymocytes. Trav15-dv6 family Tcrd rearrangements are critical for Tcra repertoire formation because of their central and distal locations in the Va-Vd array.

2021-10-21 | GSE186044 | GEO

Dynamic Chromatin Boundaries of TCR Loci Coincide V(D)J recombination During T Cell Development

Project description:Topologically Associating Domains (TADs) partition the genome into self-interacting regions through boundaries. Chromatin configuration plays a crucial role in TCR gene rearrangements, thereby affecting repertoire diversity. To assess the dynamics of chromatin boundaries within TCR genes, we conducted Hi-C assays on double-negative (DN) and double-positive (DP) cells from RAG-deficient mice. A chromatin boundary at the 3' end of the Tcrb locus observed in DN cells dissipated in DP cells, thereby altering interactions between the main Vβ cluster and the recombination center. Additionally, the INTs boundary in the Tcra-Tcrd locus disappeared in DP cells, leading to enhanced interactions between the proximal Vα region and recombination center at the Jα segments. Subsequent analysis revealed that the disappearance of boundaries was not attributable to diminished CTCF binding but rather heightened activity within these regions. This study illuminates the developmental dynamics of TAD boundaries in TCR genes, enriching our understanding of their evolving nature.

2024-04-27 | GSE265888 | GEO

Orientation-specific RAG activity in chromosomal loop domain contribute to Tcrd V(D)J recombination during T cell development

Project description:T cell antigen receptor Î´ (Tcrd) variable region exons are assembled by RAG-initiated V(D)J recombination. Here, we employ a high throughput method to map hundreds of thousands of RAG-initiated Tcrd D segment (Trdd1 and Trdd2) rearrangements in developing thymocytes. We find that Trdd2 joins directly to Trdv, Trdd1, and Trdj segments, but Trdd1 joining is ordered with joining to Trdd2 a prerequisite for further rearrangement. We also find frequent, previously unappreciated Trdd1 and Trdd2 rearrangements that inactivate Tcrd. Moreover, we find numerous RAG off-targets that are generated via unidirectional RAG tracking across the loop-domain containing Trdd1, Trdd2 and Trdj. Correspondingly, disruption of the upstream domain boundary causes spreading of on- and off-target RAG activity to the proximal Trdv domain. RAG-initiatd Tcrd D segment rearrangements in developing thymocytes were generated by deep sequencing using illumine Miseq

2016-08-04 | E-GEOD-79892 | biostudies-arrayexpress

Molecular mechanism underline immune cell type population shift upon anti-DLL4 treatment

Project description:Molecular mechanism underline immune cell type population shift upon anti-DLL4 treatment C57BL/6 mice were injected with anti-DLL4, or an isotype control antibody as controls. Two weeks later mice were sacrificed, and thymi was harvested from 4 anti-DLL4 and 4 control animals. Total thymocytes, DN cells (CD4-CD8-) and DN1(CD4-CD8- CD44+CD25-) cells were isolated. Samples included in this data set are: 3 Thymocytes-anti-DLL4; 3 Thymocytes-isotype control; 3 DN1-anti-DLL4; 2 DN1-isotype controls; 3 DN-anti-DLL4; 3 DN-isotyoe control.

2012-04-29 | E-GEOD-24296 | biostudies-arrayexpress

Role of AhR in thymocyte emigration in vivo

Project description:Over-activation of the aryl hydrocarbon receptor by TCDD in mice leads among other phenotypes to a severe thymic atrophy accompanied by immunosuppression. TCDD causes a block in thymocyte maturation and a preferential emigration of immature CD4-CD8- DN thymocytes (recent thymic emigrants) into the periphery. As part of this study gene expression profiles from DN thymocytes and thymic emigrants were generated from TCDD and solvent control mice Keywords: Affymetrix, TCDD, CD4-CD8- thymocytes, Thymus involution, thymic emigration, Ahr Female, 6-8 week old C57BL6 mice were i.p. injected with 10 M-BM-5g/kg TCDD. After 5 days mice were anesthezised and FITC injected into their thymi. after 24h mice were sacrificed and CD4-CD8-FITC+ cells isolated from thymus (thymocytes) and spleen (recent thymus emigrants).

2008-11-25 | E-GEOD-10166 | biostudies-arrayexpress

An ectopic CTCF binding element disturbs VÎ´ usage at the mouse Tcra-Tcrd locus by regulating contact between VÎ´ and DÎ´ gene segments

Project description:Chromatin looping mediated by the CCCTC binding factor CTCF regulates V(D)J recombination at antigen receptor loci. CTCF-mediated looping can influence recombination signal sequence accessibility by regulating enhancer activation of germline promoters. CTCF-mediated looping has also been shown to limit directional tracking of the RAG recombinase along chromatin, and to regulate through-space interactions between recombination signal sequences, independent of the RAG recombinase. However, in all prior instances in which CTCF-mediated looping was shown to influence V(D)J recombination, it was not possible to fully resolve the relative contributions to the V(D)J recombination phenotype of changes in accessibility, RAG-tracking, and RAG-independent long-distance interactions. Here, to assess mechanisms by which CTCF-mediated looping can impact V(D)J recombination, we introduced an ectopic CTCF binding element (CBE) immediately downstream of EÎ´ in the murine Tcra-Tcrd locus. The ectopic CBE impaired inversional rearrangement of Trdv5 in the absence of measurable effects on Trdv5 transcription and chromatin accessibility. Moreover, although the ectopic CBE limited directional RAG tracking from the Tcrd recombination center, such tracking cannot account for Trdv5-to-Trdd2 inversional rearrangement. Rather, the defect in Trdv5 rearrangement could only be attributed to a reconfigured chromatin loop organization that limited RAG-independent through-space interactions between the Trdv5 and Trdd2 RSSs. We conclude that CTCF can regulate V(D)J recombination by segregating RSSs into distinct loop domains and inhibiting RSS synapsis, independent of any effects on transcription, RSS accessibility and RAG tracking. RAG-initiatd Tcrd D segment rearrangements in developing thymocytes were generated by deep sequencing using illumine Miseq

2016-09-02 | E-GEOD-81351 | biostudies-arrayexpress

Role of AhR in thymocyte emigration in vivo

2008-11-25 | GSE10166 | GEO

Three-way contact analysis characterizes the higher-order organization of the Tcra locus

Project description:The generation of highly diverse antigen receptors in T and B lymphocytes relies on V(D)J recombination. The enhancer Eα has been implicated in regulating the accessibility of Vα and Jα genes through long-range interactions during T cell antigen receptor gene Tcra rearrangements. However, direct evidence for Eα physically mediating the interaction of Vα and Jα genes is still lacking. In this study, we utilized the 3C-HTGTS assay, a chromatin interaction technique based on 3C, to analyze the higher-order chromatin structure of the Tcra locus. Our analysis revealed the presence of sufficient information in the 3C-HTGTS data to detect multi-way contacts. Three-way contact analysis of the Tcra locus demonstrated the co-occurrence of the proximal Jα genes, Vα genes, and Eα in CD4+CD8+ double-positive thymocytes. Notably, the INT2-TEAp loop emerged as a prominent structure likely responsible for bringing the proximal Jα genes and the Vα genes into proximity. Moreover, the enhancer Eα utilizes this loop to establish physical proximity with the proximal Vα gene region. This study provides insights into the higher-order chromatin structure of the Tcra locus, shedding light on the spatial organization of chromatin and its impact on V(D)J recombination.

2022-11-28 | GSE214918 | GEO

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