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Multiway chromatin conformation analyses at the human immunoglobulin heavy chain locus reveal regulatory principles underlying somatic hypermutation [ATAC-Seq]

ABSTRACT: The generation of protective antibodies by somatic hypermutation (SHM) is essential for antibody maturation and adaptive immunity. SHM involves co-transcriptional mutagenesis of immunoglobulin variable (V) regions regulated by enhancers located hundreds of kilobases away. How 3D chromatin structure affects SHM is poorly understood. Here, we measure higher-order interactions on single alleles of the human immunoglobulin heavy chain locus (IGH) using Tri-C. We find that SHM is underpinned by a multiway hub wherein the V region is proximal to all enhancers. Cohesin-mediated loop extrusion is dispensable for IGH transcription and hub architecture. Transcription and mutagenesis of IGH switch regions, which are necessary for antibody class-switch recombination, creates new chromatin loops that can form without cohesin. However, these additional loops do not compromise hub integrity, V region transcription or SHM. Thus, antibody maturation occurs within a multiway hub accommodating several gene-enhancer loops wherein transcription and mutagenesis of different segments can occur non-competitively.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271541 | GEO | 2025/06/16

REPOSITORIES: GEO

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Multiway chromatin conformation analyses at the human immunoglobulin heavy chain locus reveal regulatory principles underlying somatic hypermutation [Tri-C]

Project description:The generation of protective antibodies by somatic hypermutation (SHM) is essential for antibody maturation and adaptive immunity. SHM involves co-transcriptional mutagenesis of immunoglobulin variable (V) regions regulated by enhancers located hundreds of kilobases away. How 3D chromatin structure affects SHM is poorly understood. Here, we measure higher-order interactions on single alleles of the human immunoglobulin heavy chain locus (IGH) using Tri-C. We find that SHM is underpinned by a multiway hub wherein the V region is proximal to all enhancers. Cohesin-mediated loop extrusion is dispensable for IGH transcription and hub architecture. Transcription and mutagenesis of IGH switch regions, which are necessary for antibody class-switch recombination, creates new chromatin loops that can form without cohesin. However, these additional loops do not compromise hub integrity, V region transcription or SHM. Thus, antibody maturation occurs within a multiway hub accommodating several gene-enhancer loops wherein transcription and mutagenesis of different segments can occur non-competitively.

2025-06-20 | GSE273433 | GEO

Multiway chromatin conformation analyses at the human immunoglobulin heavy chain locus reveal regulatory principles underlying somatic hypermutation [PRO-Seq]

2025-06-16 | GSE273431 | GEO

Multiway chromatin conformation analyses at the human immunoglobulin heavy chain locus reveal regulatory principles underlying somatic hypermutation [MutPE-Seq]

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Multiway chromatin conformation analyses at the human immunoglobulin heavy chain locus reveal regulatory principles underlying somatic hypermutation [ChIP-Seq]

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Genome-wide localization of Smc1, Smc3 and CTCF in mouse B cells.

Project description:Immunoglobulin class switch recombination (CSR) is initiated by the transcription-coupled recruitment of activation induced cytidine deaminase (AID) to switch regions and by the subsequent generation and resolution of dsDNA breaks (DSBs). During, CSR the IgH locus undergoes dynamic three-dimensional structural changes in which promoters, enhancers and switch regions are brought to close proximity. Nevertheless, little is known about the underlying mechanisms. Here we show that during CSR, AID associates with subunits of cohesin, a complex previously implicated in DNA repair and in the formation of DNA loops between enhancers and promoters. By ChIP-Seq experiments, we find that Cohesin is dynamically recruited to the IgH locus during CSR and that knockdown of Cohesin or its regulatory subunits results in impaired CSR and abnormal DSB resolution. Our results are consistent with a model in which Cohesin controls the formation of long-range DNA loops at the IgH locus and the resolution of DSBs generated during CSR. Smc1, Smc3 and CTCF were immunoprecipitated from resting or in vitro activated B cells.

2013-10-11 | E-GEOD-43594 | biostudies-arrayexpress

Genome-wide localization of Smc1, Smc3 and CTCF in mouse B cells.

2013-10-11 | GSE43594 | GEO

HIRA-dependent H3.3 deposition and its modification H3.3K36me3 facilitate somatic hypermutation of immunoglobulin genes by maintaining the proper chromatin state and transcription

Project description:The H3.3 histone variant and its chaperone HIRA are involved in active transcription but their detailed roles in regulating somatic hypermutation (SHM) of immunoglobulin variable regions in human B cells is not yet fully understood. In this study we show that, knockout (KO) of HIRA significantly decreased SHM and changed the mutation pattern of the variable region of immunoglobulin heavy chain (IGH) in the human Ramos B cell line without changing the levels of AID and other major proteins known to be involved in SHM. Except for H3K79me2/3, many factors related to active transcription, including H3.3, were substantively decreased in HIRA KO cells and this was accompanied by decreased nascent transcription in IGH locus. The abundance of ZMYND11 that specifically binds to H3.3K36me3 on the Ig locus was also reduced in the HIRA KO. Somewhat surprisingly HIRA loss increased the chromatin accessibility of Ig V region locus. Furthermore, stable expression of ectopic H3.3G34V and H3.3G34R mutants that inhibit both the trimethylation of H3.3K36 and the recruitment of ZMYND11 significantly reduced SHM in Ramos cells, while the H3.3K79M did not. Consistent with HIRA KO, the H3.3G34V mutant also decreased the occupancy of various elongation factors and of ZMYND11 on the IGH variable and downstream switching regions. Our results reveal an unrecognized role of HIRA and the H3.3K36me3 modification in SHM and extend our knowledge of how transcription coupled chromatin structure and accessibility contribute to SHM in human B cells.

2021-07-29 | GSE180899 | GEO

The Chromatin Reader ZMYND8 Regulates Igh Enhancers to Promote Immunoglobulin Class Switch Recombination

Project description:Class Switch Recombination (CSR) is a DNA recombination reaction that diversifies the effector component of antibody responses. CSR is initiated by activation-induced cytidine deaminase (AID), which targets transcriptionally active immunoglobulin heavy chain (Igh) switch donor and acceptor DNA. The 3’ Igh super-enhancer, 3’ Regulatory Region (3’RR), is essential for acceptor region transcription, but how this function is regulated is unknown. Here we identify the chromatin reader ZMYND8 as an essential regulator of the 3’RR and CSR. In B cells, ZMYND8 binds promoters and super-enhancers, including the 3’RR, and controls its activity by modulating the enhancer transcriptional status. In its absence, there is increased 3’RR polymerase loading, and decreased acceptor region transcription and CSR. In addition to CSR, ZMYND8 deficiency impairs somatic hypermutation (SHM) of Igh, which is also dependent on the 3’RR. Thus ZMYND8 controls Igh diversification in mature B lymphocytes by regulating the activity of the 3’ Igh super-enhancer.

2018-10-04 | GSE118794 | GEO

Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation

Project description:Somatic hypermutation (SHM) introduces point mutations into immunoglobulin (Ig) genes of activated B cells to support the process of antibody affinity maturation but also causes "off-target" mutations in other parts of the genome. We have used sensitive lentiviral SHM reporter vectors and a mutationally active human B cell line to identify dozens of regions of the genome that are intrinsically susceptible to SHM ("hot" regions) and many hundreds of regions that are resistant to SHM ("cold" regions). Hot and cold regions are frequently contained within topologically associated domains (TADs). Comparison of hot and cold TADs reveals that while overall levels of transcription are equal, hot TADs are enriched for NIPBL (a component of the cohesin loader), super enhancers, markers of paused/stalled RNA polymerase 2, and multiple transcription factors implicated in B cell development and targeting of SHM. We demonstrate that at least some hot TADs contain enhancer elements that possess SHM targeting activity and that insertion of a strong Ig SHM-targeting element into a cold TAD renders it hot. Our findings lead to a model for SHM susceptibility involving the cooperative action of cis-acting SHM targeting elements and the dynamic and architectural properties of TADs.

2019-12-04 | GSE139810 | GEO

Wapl repression by Pax5 promotes loop extrusion and V gene recombination at the Igh locus

Project description:The generation of a diverse antibody repertoire is essential for humoral immunity and requires the participation of all V genes in V(D)J recombination, which depends on the Pax5-regulated contraction of the 2.8-Mb long immunoglobulin heavy-chain (Igh) locus. How Pax5 controls Igh contraction in pro-B cells is, however, not known. Here, we demonstrate that locus contraction is caused by cohesin-mediated chromatin loop extrusion across the entire Igh locus. Notably, expression of the cohesin-release factor Wapl is repressed by Pax5 specifically in pro-B and pre-B cells, which facilitates extended loop extrusion by increasing the residence time of cohesin on chromatin. Pax5 mediates the transcriptional repression of Wapl through a single Pax5-binding site by recruiting the Polycomb repressive complex 2 to induce bivalent chromatin at the Wapl promoter. Reduced Wapl expression causes global alterations of the three-dimensional chromatin architecture, indicating that the potential to recombine all V genes entails structural changes of the entire genome in pro-B cells.

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