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Contribution of IGCR1 and 3' CBE Super Anchor to Developmental Regulation of Igh V(D)J Recombination

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE230605 | GEO | 2023/05/30

REPOSITORIES: GEO

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Contribution of IGCR1 and 3' CBE Super Anchor to Developmental Regulation of Igh V(D)J Recombination [3C_HTGTS_Seq]

Project description:Immunoglobulin heavy chain variable region exons are assembled in progenitor-B cells, from VH, D, and JH gene segments located in separate clusters across the Igh locus. RAG endonuclease orchestrates V(D)J recombination from a JH-based recombination center (RC). Cohesin-mediated extrusion of upstream chromatin past RC-bound RAG presents Ds for joining to JHs to form a DJHRC, from which RAG scans upstream for VHs to assemble VHDJH exons in an ordered recombination process. Cohesin-mediated chromatin loop extrusion is impeded by CTCF-bound elements (CBEs), with extrusion between two CBEs, particularly if convergently-oriented, forming chromatin-contact loops genome-wide. Igh has provocative CBE organization, with two divergently-oriented CBEs (CBE1 and CBE2) in the IGCR1 element between the VH and D/JH domains, dozens of VH domain CBEs convergent to CBE1, and 10 3'Igh-CBEs convergent to CBE2. IGCR1 CBEs segregate D/JH and VH domains by impeding RAG-scanning. After DJH formation, down-regulation of WAPL, a cohesin unloader, neutralizes IGCR1 and VH-domain CBEs, allowing RAG to scan the VH domain. To elucidate potential mechanisms underlying the developmental transition from D-to-JH to VH-to-DJH recombination and potential roles of IGCR1-based CBEs and 3'Igh-CBEs in regulating RAG-scanning, we tested effects of deleting or inverting IGCR1 or 3'Igh-CBEs in mice and/or progenitor-B cell lines. These studies revealed that normal IGCR1 CBE orientation augments its RAG-scanning impediment activity and that the 3'Igh-CBEs reinforce RC activity as a dynamic loop extrusion impediment, thereby, increasing its ability to support V(D)J recombination. Finally, our findings implicate a mechanism by which developmental WAPL down-regulation contributes to ordered V(D)J recombination.

2023-05-30 | GSE230604 | GEO

Contribution of IGCR1 and 3' CBE Super Anchor to Developmental Regulation of Igh V(D)J Recombination [HTGTS_VDJ_Seq]

2023-05-30 | GSE230251 | GEO

Contribution of IGCR1 and 3' CBE Super Anchor to Developmental Regulation of Igh V(D)J Recombination [GRO_Seq]

2023-05-30 | GSE230249 | GEO

Contribution of IGCR1 and 3' CBE Super Anchor to Developmental Regulation of Igh V(D)J Recombination

Project description:Contribution of IGCR1 and 3' CBE Super Anchor to Developmental Regulation of Igh V(D)J Recombination

| PRJNA961836 | ENA

Contribution of IGCR1 and 3' CBE Super Anchor to Developmental Regulation of Igh V(D)J Recombination [HTGTS_VDJ_Seq]

Project description:Contribution of IGCR1 and 3' CBE Super Anchor to Developmental Regulation of Igh V(D)J Recombination [HTGTS_VDJ_Seq]

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Contribution of IGCR1 and 3' CBE Super Anchor to Developmental Regulation of Igh V(D)J Recombination [GRO_Seq]

Project description:Contribution of IGCR1 and 3' CBE Super Anchor to Developmental Regulation of Igh V(D)J Recombination [GRO_Seq]

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Contribution of IGCR1 and 3' CBE Super Anchor to Developmental Regulation of Igh V(D)J Recombination [3C_HTGTS_Seq]

Project description:Contribution of IGCR1 and 3' CBE Super Anchor to Developmental Regulation of Igh V(D)J Recombination [3C_HTGTS_Seq]

| PRJNA961843 | ENA

Physiological role of the 3'IgH CBEs super-anchor in antibody class switching.

Project description:IgH class switch recombination (CSR) replaces Cμ constant region (CH) exons with one of six downstream CHs by joining transcription-targeted double-strand breaks (DSBs) in the Cμ switch (S) region to DSBs in a downstream S region. Chromatin loop extrusion underlies fundamental CSR mechanisms including 3'IgH regulatory region (3'IgHRR)-mediated S region transcription, CSR center formation, and deletional CSR joining. There are 10 consecutive CTCF-binding elements (CBEs) downstream of the 3'IgHRR, termed the "3'IgH CBEs." Prior studies showed that deletion of eight 3'IgH CBEs did not detectably affect CSR. Here, we report that deletion of all 3'IgH CBEs impacts, to varying degrees, germline transcription and CSR of upstream S regions, except that of Sγ1. Moreover, deletion of all 3'IgH CBEs rendered the 6-kb region just downstream highly transcribed and caused sequences within to be aligned with Sμ, broken, and joined to form aberrant CSR rearrangements. These findings implicate the 3'IgH CBEs as critical insulators for focusing loop extrusion-mediated 3'IgHRR transcriptional and CSR activities on upstream CH locus targets.

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ERG controls B-cell development by promoting Igh V-to-DJ recombination

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-11-24 | GSE128978 | GEO

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Project description:This SuperSeries is composed of the SubSeries listed below.

2022-07-20 | GSE197956 | GEO