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A Unifying Model for Molecular Determinants of the Pre-selection Vb Repertoire [RNA-Seq]

ABSTRACT: 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 have quantified Vβ usage in the pre-selection Tcrb repertoire and report relative contributions of 14 distinct features in shaping their recombination efficiencies, including transcription, chromatin environment, spatial proximity to their DβJβ targets, and quality of recombinase recognition elements. Computational analyses provide a unifying model, revealing a minimal set of eight parameters that are predictive of Vβusage, dominated by chromatin modifications associated with transcription, but largely independent of the precise spatial proximity to DβJβclusters.

ORGANISM(S): Mus musculus

PROVIDER: GSE49233 | GEO | 2013/08/14

SECONDARY ACCESSION(S): PRJNA213620

REPOSITORIES: GEO

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A Unifying Model for Molecular Determinants of the Pre-selection Vb Repertoire [RNA-Seq]

Project description: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 have quantified Vβ usage in the pre-selection Tcrb repertoire and report relative contributions of 14 distinct features in shaping their recombination efficiencies, including transcription, chromatin environment, spatial proximity to their DβJβ targets, and quality of recombinase recognition elements. Computational analyses provide a unifying model, revealing a minimal set of eight parameters that are predictive of Vβusage, dominated by chromatin modifications associated with transcription, but largely independent of the precise spatial proximity to DβJβclusters. Transcription profiles of mouse DN thymocytes from Rag1 KO mice were generated by deep sequencing, using Illumina Hi-Seq 2000.

2013-08-14 | E-GEOD-49233 | biostudies-arrayexpress

A Unifying Model for Molecular Determinants of the Pre-selection Vβ Repertoire [ChIP-chip]

Project description:Chip-chip from pro-T(DN) cells from Rag1KO mice for H3K27ac, P300 and FAIRE 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 have quantified Vβ usage in the pre-selection Tcrb repertoire and report relative contributions of 14 distinct features in shaping their recombination efficiencies, including transcription, chromatin environment, spatial proximity to their DβJβ targets, and quality of recombinase recognition elements. Computational analyses provide a unifying model, revealing a minimal set of eight parameters that are predictive of Vβusage, dominated by chromatin modifications associated with transcription, but largely independent of the precise spatial proximity to DβJβclusters.

2013-08-14 | GSE42851 | GEO

A Unifying Model for Molecular Determinants of the Pre-selection VÎ² Repertoire [ChIP-chip]

Project description:Chip-chip from pro-T(DN) cells from Rag1KO mice for H3K27ac, P300 and FAIRE 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 have quantified VÎ² usage in the pre-selection Tcrb repertoire and report relative contributions of 14 distinct features in shaping their recombination efficiencies, including transcription, chromatin environment, spatial proximity to their DÎ²JÎ² targets, and quality of recombinase recognition elements. Computational analyses provide a unifying model, revealing a minimal set of eight parameters that are predictive of VÎ²usage, dominated by chromatin modifications associated with transcription, but largely independent of the precise spatial proximity to DÎ²JÎ²clusters. Rag1KO DN epigenetic landscape at Tcrb

2013-08-14 | E-GEOD-42851 | biostudies-arrayexpress

Locus folding mechanisms determine modes of antigen receptor gene assembly (ChIP-seq)

Project description:The dynamic folding of genomes regulates numerous biological processes, including antigen receptor (AgR) gene assembly. We show that, unlike other AgR loci, homotypic chromatin interactions and bi-directional chromosome looping both contribute to structuring Tcrb for efficient long-range V(D)J recombination. Inactivation of the CTCF binding element (CBE) or promoter at the most 5’Vβ segment (Trbv1) impaired loop extrusion originating locally and extending to DβJβ CBEs at the opposite end of Tcrb. Promoter or CBE mutation nearly eliminated Trbv1 contacts and decreased RAG endonuclease-mediated Trbv1 recombination. Importantly, Trbv1 rearrangement can proceed independent of substrate orientation, ruling out scanning by DβJβ-bound RAG as the sole mechanism of Vβ recombination, distinguishing it from Igh. Our data indicate that CBE-dependent generation of loops cooperates with promoter-mediated activation of chromatin to juxtapose Vβ and DβJβ segments for recombination through diffusion-based synapsis. Thus, the mechanisms that fold a genomic region can influence molecular processes occurring in that space, which may include recombination, repair, and transcriptional programming.

2024-01-04 | GSE249647 | GEO

Locus folding mechanisms determine modes of antigen receptor gene assembly (Hi-C)

2024-01-04 | GSE249646 | GEO

Locus folding mechanisms determine modes of antigen receptor gene assembly (RNA-seq)

2024-01-04 | GSE249648 | 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

The endogenous retrovirus Mtv8 which resides within the V kappa locus does not influence the mouse immunoglobulin repertoire

Project description:The vast diversity of mammalian adaptive antigen receptors allows for robust and efficient immune responses against a wide number of pathogens. The antigen receptor repertoire is built during the recombination and hypermutation of B and T cell receptor (B-, TCR) loci. V(D)J recombination rearranges these antigen receptor loci which are organized as an array of separate V, (D), and J gene segments. Which gene segments are recombined, and thus which particular antigen receptors are present in the host repertoire, depends on the three-dimensional architecture of the recombining locus. The endogenous retrovirus (ERV) mouse mammary tumor provirus (Mtv8) resides on mouse chromosome 6 interposed within the large array of light chain kappa (IgK) V gene segments. It was unknown, however, whether Mtv8 influences the BCR repertoire, as ERVs can contribute to changes in genomic architecture by driving high levels of local transcription. We generated Mtv8-deficient mice to determine if the ERV influenced V(D)J recombination and found no significant difference in the peripheral BCR repertoire of Mtv8-deficient mice compared to wildtype controls. Thus, Mtv8, the endogenous retrovirus in the Igk locus, does not influence BCR repertoires.

2023-11-27 | GSE248410 | GEO

HIGHLY DIVERSE TCRalpha CHAIN REPERTOIRE OF PRE-IMMUNE CD8+ T CELLS REVEALS NEW INSIGHTS IN GENE RECOMBINATION

Project description:By sequencing tens of millions of TCR? chain transcripts from naïve mouse CD8+ T cells, we observed a hugely diverse repertoire, comprising nearly all possible TRAV-TRAJ combinations. Our findings are not compatible with sequential coordinate gene recombination, but rather with a model in which contraction and DNA looping in the TCR?? locus provide equal access to TRAV and TRAJ gene segments, similar to that demonstrated for IgH gene recombination High-throughput sequencing of entire TCRa repertoire from C57Bl/6 mice

2012-02-09 | E-GEOD-35626 | biostudies-arrayexpress

HIGHLY DIVERSE TCRalpha CHAIN REPERTOIRE OF PRE-IMMUNE CD8+ T CELLS REVEALS NEW INSIGHTS IN GENE RECOMBINATION

Project description:By sequencing tens of millions of TCRα chain transcripts from naïve mouse CD8+ T cells, we observed a hugely diverse repertoire, comprising nearly all possible TRAV-TRAJ combinations. Our findings are not compatible with sequential coordinate gene recombination, but rather with a model in which contraction and DNA looping in the TCRαδ locus provide equal access to TRAV and TRAJ gene segments, similar to that demonstrated for IgH gene recombination

2012-02-09 | GSE35626 | GEO

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