Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA380816 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5388300_1.fastq.gz | Fastqsanger.gz | |||
| SRR5388300_2.fastq.gz | Fastqsanger.gz | |||
| SRR5388310_1.fastq.gz | Fastqsanger.gz | |||
| SRR5388310_2.fastq.gz | Fastqsanger.gz | |||
| SRR5388320_1.fastq.gz | Fastqsanger.gz |
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Project description:Antigen receptor gene recombination requires stochastic, monoallelic choice of a single variable gene in each lymphocyte progenitor. However, how this occurs remains unknown. Herein, we report that prior to Vκ to Jκ gene recombination, Igκ alleles reside within spatially different nuclear niches defined by elongating RNA Polymerase II (e-Pol II) and cyclin D3 complexes assembled on the nuclear matrix. Upon cell cycle exit, and cyclin D3 downregulation, only the Vκ allele in the more constrained e-Pol II niche was transcribed. Chromatin modeling and single cell RNA-seq revealed that the nuclear niche favored Vκ flanking CTCF sites, thus shaping the transcribed repertoire. Furthermore, multiple contiguous Vκs oriented away from CTCF sites were preferentially transcribed. Cyclin D3 also repressed monoallelic protocadherin and olfactory genes. These studies of Igκ reveal a general mechanism by which regulated, stochastic chromatin loop capture by fixed e-Pol II complexes generates diversity and couples cell cycle exit to monogenic choice.
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Project description:Although much research has been done to understand how rearrangement of the Igκ locus is regulated during B-cell development, very little is known about the way the variable (V) segments themselves are selected. Using B6/Cast hybrid pre-B cell clones, we show that a limited number of V segments on each allele is stochastically activated as characterized by the appearance of ncRNA and histone modifications. The activation states are clonally distinct, stable across cell division and developmentally important in directing the Ig repertoire upon differentiation. By employing a new approach of allelic ATAC-seq we demonstrate that the Igκ V alleles have differential chromatin accessibility, which may serve as the underlying basis of clonal maintenance at this locus, as well as other instances of monoallelic expression throughout the genome. These findings highlight a new level of immune-system regulation that appears to be geared at optimizing gene diversity.
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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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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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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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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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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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