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CTCF-mediated chromatin topology enables receptor editing to enforce a central B-cell tolerance checkpoint [RNA-seq]

ABSTRACT: The generation of a diverse yet self-tolerant B cell repertoire is fundamental to adaptive immunity and is achieved through the ordered process of V(D)J recombination. In mice, Igκ represents the dominant light chain, while Igλ rearrangement serves as a secondary response to nonproductive or autoreactive Igκ recombination — a process known as receptor editing. Recombination at the RS element deletes the Igκ constant exon, silencing the locus and enabling Igλ expression. Yet the epigenetic regulatory framework that orchestrates this critical tolerance checkpoint in immature B cells remains unresolved. Here, we identify a CTCF-binding element (CBE) embedded within the 3′-Igκ super-enhancer (3′-SEκ) that governs receptor editing and directs the κ-to-λ switch essential for Igλ⁺ B cell development in vivo. Mechanistically, deletion of this insulator element abrogates chromatin looping essential for receptor editing and concomitantly activates a latent enhancer program within the 3′-SEκ, driving aberrant Vκ recombination and rewiring Igκ chromatin architecture through disrupted CTCF boundary function. Notably, loss of this CBE swiftly leads to elevated autoantibody production, demonstrating that CBE-mediated chromatin architecture shapes B cell fate by constraining autoreactivity. Collectively, these findings establish CTCF-dependent chromatin topology as a checkpoint that couples three-dimensional genome organization with antigen-driven receptor editing, to establish self-tolerance.

ORGANISM(S): Mus musculus

PROVIDER: GSE313430 | GEO | 2026/01/15

REPOSITORIES: GEO

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CTCF-mediated chromatin topology enables receptor editing to enforce a central B-cell tolerance checkpoint [RNA-seq_IGK repertoire]

Project description:The generation of a diverse yet self-tolerant B cell repertoire is fundamental to adaptive immunity and is achieved through the ordered process of V(D)J recombination. In mice, Igκ represents the dominant light chain, while Igλ rearrangement serves as a secondary response to nonproductive or autoreactive Igκ recombination — a process known as receptor editing. Recombination at the RS element deletes the Igκ constant exon, silencing the locus and enabling Igλ expression. Yet the epigenetic regulatory framework that orchestrates this critical tolerance checkpoint in immature B cells remains unresolved. Here, we identify a CTCF-binding element (CBE) embedded within the 3′-Igκ super-enhancer (3′-SEκ) that governs receptor editing and directs the κ-to-λ switch essential for Igλ⁺ B cell development in vivo. Mechanistically, deletion of this insulator element abrogates chromatin looping essential for receptor editing and concomitantly activates a latent enhancer program within the 3′-SEκ, driving aberrant Vκ recombination and rewiring Igκ chromatin architecture through disrupted CTCF boundary function. Notably, loss of this CBE swiftly leads to elevated autoantibody production, demonstrating that CBE-mediated chromatin architecture shapes B cell fate by constraining autoreactivity. Collectively, these findings establish CTCF-dependent chromatin topology as a checkpoint that couples three-dimensional genome organization with antigen-driven receptor editing, to establish self-tolerance.

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CTCF-mediated chromatin topology enables receptor editing to enforce a central B-cell tolerance checkpoint [ChIP-Seq_CTCF]

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CTCF-mediated cis-regulatory chromatin insulation enforces a central B-cell tolerance checkpoint [ChIP-Seq_H3K27ac]

Project description:The generation of a diverse and self-tolerant B cell repertoire is essential for adaptive immunity and is achieved through V(D)J recombination. In mice, Igκ is the dominant light chain, whereas Igλ rearrangement typically occurs in response to nonproductive or autoreactive Igκ recombination, a process termed receptor editing. Recombination at the RS element deletes the Igκ constant exon, silencing the locus and enabling Igλ expression. However, the epigenetic regulatory framework that orchestrates and governs receptor editing remains poorly defined. Here, we identify a CTCF-binding insulator element (CBE) within the 3′ Igκ super-enhancer (3′-SEκ) that regulates receptor editing and directs the κ-to-λ switch required for Igλ⁺ B-cell development. Mechanistically, loss of this CBE activates an insulated enhancer within the 3′-SEκ, causing aberrant Vκ rearrangements and altered chromatin interactions through disrupted loop extrusion dynamics. Notably, loss of this CBE in mice leads to increased autoantibody production by ten weeks of age, demonstrating that CBE-mediated chromatin architecture shapes B cell fate by constraining autoreactive potential. Collectively, our findings define a novel CTCF-dependent cis- regulatory insulation checkpoint that connects chromatin loop extrusion to antigen- driven receptor editing, thereby enforcing B-cell tolerance.

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CTCF-mediated cis-regulatory chromatin insulation enforces a central B-cell tolerance checkpoint [ATAC-seq]

2026-01-15 | GSE313428 | GEO

Asymmetrical forward and reverse developmental trajectories determine molecular programs of B cell antigen receptor editing

Project description:During B lymphopoiesis, B cell progenitors progress through alternating and mutually exclusive stages of clonal expansion and immunoglobulin (Ig) gene rearrangements. Great diversity is generated through the stochastic recombination of Ig gene segments encoding heavy and light chain variable domains. However, this commonly generates autoreactivity. Receptor editing is the predominant tolerance mechanism for self-reactive B cells in the bone marrow (BM). B cell receptor editing rescues autoreactive B cells from negative selection through renewed light chain recombination first at Igκ then Igλ loci. Receptor editing depends upon BM microenvironment cues and key transcription factors such as Nuclear factor kappa B, Forkhead box protein O and Transcription Factor 3. The specific BM factor required for receptor editing is unknown. Furthermore, how transcription factors coordinate these developmental programs to promote usage of the λ-chain remain poorly defined. Therefore, we utilized two mouse models that recapitulate pathways by which Igλ light chain positive B cells develop. The first possess deleted J kappa (Jκ) genes and, as such, models Igκ expression resulting from failed Igκ recombination (Igκdel). The second models autoreactivity by ubiquitous expression of a single-chain chimeric anti-Igκ antibody (κ-mac). Here, we demonstrated that autoreactive B cells transit asymmetric forward and reverse developmental trajectories. This imparted a unique epigenetic landscape on small pre-B cells, which opened chromatin to transcription factors essential for Igλ recombination. The consequences of this asymmetric developmental path were both amplified and complemented by CXCR4 signaling. These findings reveal how intrinsic molecular programs integrate with extrinsic signals to drive receptor editing.

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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

An ectopic CTCF binding element disturbs Vδ usage at the mouse Tcra-Tcrd locus by regulating contact between Vδ and Dδ 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 Eδ 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.

2016-09-02 | GSE81351 | GEO

CTCF couples long-range loop extrusion and diffusional mechanism to mediate a diverse Igk repertoire

Project description:Dynamic genome folding plays a crucial role in cellular functions, including V(D)J recombination at the immunoglobulin kappa (Igκ) locus for antibody generation. This process involves frequent recombination between Jκ and Vκ gene segments over a 3.2 Mb region in both deletional and inversional orientations. While loop extrusion and diffusion are thought to facilitate Igκ recombination, their cooperative mechanisms remain unclear. Our study demonstrates CTCF as a key regulator coupling loop extrusion and diffusion to enhance Vκ recombination in both orientations across large genomic distances. We show that CTCF's N-terminus promotes long-range loop extrusion important for distal Vκ usage by stabilizing cohesin against Wapl release. Furthermore, CTCF's loop barrier function is essential for inversional Vκ usage via enabling diffusion. In CTCF N-terminus mutants, defects in inversional Vκ joining were not corrected by Wapl depletion alone but improved with targeted dCas9 blockade mimicking the CTCF barrier. These findings reveal that CTCF regulates immune diversity via diverse mechanisms and underscore its versatility in gene regulation.

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