Dataset Information

Flexible long-range loops in the VH gene region of the Igh locus facilitate the generation of a diverse antibody repertoire.

ABSTRACT: The immunoglobulin heavy-chain (Igh) locus undergoes large-scale contraction in pro-B cells, which facilitates VH-DJH recombination by juxtaposing distal VH genes next to the DJH-rearranged gene segment in the 3' proximal Igh domain. By using high-resolution mapping of long-range interactions, we demonstrate that local interaction domains established the three-dimensional structure of the extended Igh locus in lymphoid progenitors. In pro-B cells, these local domains engaged in long-range interactions across the Igh locus, which depend on the regulators Pax5, YY1, and CTCF. The large VH gene cluster underwent flexible long-range interactions with the more rigidly structured proximal domain, which probably ensures similar participation of all VH genes in VH-DJH recombination to generate a diverse antibody repertoire. These long-range interactions appear to be an intrinsic feature of the VH gene cluster, because they are still generated upon mutation of the E? enhancer, IGCR1 insulator, or 3' regulatory region in the proximal Igh domain.

SUBMITTER: Medvedovic J

PROVIDER: S-EPMC4810778 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Flexible long-range loops in the VH gene region of the Igh locus facilitate the generation of a diverse antibody repertoire.

Medvedovic Jasna J Ebert Anja A Tagoh Hiromi H Tamir Ido M IM Schwickert Tanja A TA Novatchkova Maria M Sun Qiong Q Huis In 't Veld Pim J PJ Guo Chunguang C Yoon Hye Suk HS Denizot Yves Y Holwerda Sjoerd J B SJ de Laat Wouter W Cogné Michel M Shi Yang Y Alt Frederick W FW Busslinger Meinrad M

Immunity 20130801 2

The immunoglobulin heavy-chain (Igh) locus undergoes large-scale contraction in pro-B cells, which facilitates VH-DJH recombination by juxtaposing distal VH genes next to the DJH-rearranged gene segment in the 3' proximal Igh domain. By using high-resolution mapping of long-range interactions, we demonstrate that local interaction domains established the three-dimensional structure of the extended Igh locus in lymphoid progenitors. In pro-B cells, these local domains engaged in long-range intera ...[more]

PMID: 23973221

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Project description:Non-coding sense and antisense germline transcription within the immunoglobulin heavy chain locus precedes V(D)J recombination and has been proposed to be associated with Igh locus accessibility, although its precise role remains elusive. However, no global analysis of germline transcription throughout the Igh locus has been done. Therefore, we performed directional RNAseq, demonstrating the locations and extent of both sense and antisense transcription throughout the Igh locus. Surprisingly, the majority of antisense transcripts are localized around two PAIR elements in the distal IghV region. Importantly, long-distance loops measured by 3C are observed between these two active PAIR promoters and Eμ, the start site of Iμ germline transcription, in a lineage- and stage-specific manner, even though this antisense transcription is Eμ-independent. YY1-/- pro-B cells are greatly impaired in distal VH gene rearrangement and Igh locus compaction, and we demonstrate that YY1 deficiency greatly reduces antisense transcription and PAIR-Eμ interactions. ChIP-seq shows high level YY1 binding only at Eμ, but low levels near some antisense promoters. PAIR-Eμ interactions are not disrupted by DRB, which blocks transcription elongation without disrupting transcription factories once they are established, but the looping is reduced after heat shock treatment, which disrupts transcription factories. We propose that transcription-mediated interactions, most likely at transcription factories, initially compact the Igh locus, bringing distal VH genes close to the DJH rearrangement, which is adjacent to Eμ. Therefore, we hypothesize that one key role of non-coding germline transcription is to facilitate locus compaction, allowing distal VH genes to undergo efficient rearrangement. In order to determine the amount and location of sense and antisense non-coding RNA in the Igh locus, we prepared total RNA from CD19+ RAG1-/- pro-B cells. Samples were either pre-enriched in custom Agilent arrays, or directly sequenced. Data from one sample for each condition is included as reflected in the publication.

Dataset Information

Flexible long-range loops in the VH gene region of the Igh locus facilitate the generation of a diverse antibody repertoire.

Publications

Flexible long-range loops in the VH gene region of the Igh locus facilitate the generation of a diverse antibody repertoire.

Similar Datasets

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