4C-ing the Igh Landscape

Nicolás, Laura; Chaudhuri, Jayanta

doi:10.1016/j.immuni.2013.08.014

Cited by 2 publications

(3 citation statements)

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“…This back-to-back orientation led us to predict that a terminus of the Igh locus might be located in this segment ( 16 ). In fact, we found additional DNase I hypersensitive sites downstream of hs4, which included hs5, 6, and 7, and has now been extended to include a CTCF-binding site, named hs8 ( 44 , 45 ). Discussions via Sandy Morse with Victor Lobanenkov introduced us to CTCF as a mammalian insulator ( 46 ), and we predicted that CTCF sites might be present in this region.…”

Section: Additional Module Downstream Of 3′ Rr Enhancers: the Ctcf-bimentioning

confidence: 82%

Epigenetic Regulation of Individual Modules of the immunoglobulin heavy chain locus 3â€² Regulatory Region

Birshtein

2014

Front. Immunol.

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The Igh locus undergoes an amazing array of DNA rearrangements and modifications during B cell development. During early stages, the variable region gene is constructed from constituent variable (V), diversity (D), and joining (J) segments (VDJ joining). B cells that successfully express an antibody can be activated, leading to somatic hypermutation (SHM) focused on the variable region, and class switch recombination (CSR), which substitutes downstream constant region genes for the originally used Cμ constant region gene. Many investigators, ourselves included, have sought to understand how these processes specifically target the Igh locus and avoid other loci and potential deleterious consequences of malignant transformation. Our laboratory has concentrated on a complex regulatory region (RR) that is located downstream of Cα, the most 3′ of the Igh constant region genes. The ~40 kb 3′ RR, which is predicted to serve as a downstream major regulator of the Igh locus, contains two distinct segments: an ~28 kb region comprising four enhancers, and an adjacent ~12 kb region containing multiple CTCF and Pax5 binding sites. Analysis of targeted mutations in mice by a number of investigators has concluded that the entire 3′ RR enhancer region is essential for SHM and CSR (but not for VDJ joining) and for high levels of expression of multiple isotypes. The CTCF/Pax5 binding region is a candidate for influencing VDJ joining early in B cell development and serving as a potential insulator of the Igh locus. Components of the 3′ RR are subject to a variety of epigenetic changes during B cell development, i.e., DNAse I hypersensitivity, histone modifications, and DNA methylation, in association with transcription factor binding. I propose that these changes provide a foundation by which regulatory elements in modules of the 3′ RR function by interacting with each other and with target sequences of the Igh locus.

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Section: Additional Module Downstream Of 3′ Rr Enhancers: the Ctcf-bimentioning

confidence: 82%

Epigenetic Regulation of Individual Modules of the immunoglobulin heavy chain locus 3â€² Regulatory Region

Birshtein

2014

Front. Immunol.

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“…In B-lineage precursors, a first contribution was assigned to CBEs, which have been proposed to facilitate interactions between locus distant regions (14,20,41,42). Deletion of hs5-7 CBEs downstream from the mouse 3′RR resulted in only a slight modification of D and V H use (16), suggesting a modest contribution of 3′ CBEs in VDJ joining, although it is not excluded that full deletion (including hs8) might have a more drastic effect (39).…”

Section: Discussionmentioning

confidence: 99%

“…Initiation of VDJ recombination is assisted by the Eμ enhancer, which provides efficient transcription and accessibility to initiate D H to J H rearrangements (7)(8)(9)(10), as well as the IGCR1 and -2 elements that ordinate the V H to DJ H second recombination step (5,(11)(12)(13). Devoid of enhancer activity (14,15), 3′CBE (hs5 to hs8) likely participate in IgH folding before VDJ recombination because deletion of hs5 to -7 only impacts use of proximal V H regions (16). In pre-B cells, once a functional H chain is expressed as a component of the pre-B-cell recptor (BCR), the Eμ enhancer function switches from DJ H region accessibility to Igμ chain expression, and consequently modulates pre-BCR expression and expansion of the pre-B-cell compartment (17,18).…”

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confidence: 99%

Sequential activation and distinct functions for distal and proximal modules within the IgH 3′ regulatory region

Garot

Marquet

Saintamand

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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As a master regulator of functional Ig heavy chain (IgH) expression, the IgH 3′ regulatory region (3′RR) controls multiple transcription events at various stages of B-cell ontogeny, from newly formed B cells until the ultimate plasma cell stage. The IgH 3′RR plays a pivotal role in early B-cell receptor expression, germ-line transcription preceding class switch recombination, interactions between targeted switch (S) regions, variable region transcription before somatic hypermutation, and antibody heavy chain production, but the functional ranking of its different elements is still inaccurate, especially that of its evolutionarily conserved quasipalindromic structure. By comparing relevant previous knockout (KO) mouse models (3′RR KO and hs3b-4 KO) to a novel mutant devoid of the 3′RR quasi-palindromic region (3′PAL KO), we pinpointed common features and differences that specify two distinct regulatory entities acting sequentially during B-cell ontogeny. Independently of exogenous antigens, the 3′RR distal part, including hs4, fine-tuned B-cell receptor expression in newly formed and naïve B-cell subsets. At mature stages, the 3′RR portion including the quasi-palindrome dictated antigen-dependent locus remodeling (global somatic hypermutation and class switch recombination to major isotypes) in activated B cells and antibody production in plasma cells.immunoglobulin gene regulation | enhancers | B-cell development I mmunoglobulin heavy chain (IgH) expression is critical for B-cell development and survival. In developing B-lineage cells, accessibility to the major remodeling events [VDJ recombination, somatic hypermutation (SHM), class switch recombination (CSR), and locus suicide recombination] depends on epigenetic changes and germ-line transcription of many regions, including V H promoters, I/switch region promoters, cis-regulatory region enhancers, and chromatin insulators (1-3). A focus on knockout (KO) models for IgH cis-regulatory regions (enhancers and chromatin insulators) is a means to simplify the regulation picture. At the preproB stage, the IgH locus undergoes long-range looping in a "rosette-like" structure that brings into close proximity major IgH regulatory regions, such as the V H to D H intergenic control regions (IGCR1 and -2), the Eμ intronic enhancer, the 3′ regulatory region (3′RR), and the 3′IgH CTCF-binding elements (CBEs) (4-6). Initiation of VDJ recombination is assisted by the Eμ enhancer, which provides efficient transcription and accessibility to initiate D H to J H rearrangements (7-10), as well as the IGCR1 and -2 elements that ordinate the V H to DJ H second recombination step (5, 11-13). Devoid of enhancer activity (14, 15), 3′CBE (hs5 to hs8) likely participate in IgH folding before VDJ recombination because deletion of hs5 to -7 only impacts use of proximal V H regions (16). In pre-B cells, once a functional H chain is expressed as a component of the pre-B-cell recptor (BCR), the Eμ enhancer function switches from DJ H region accessibility to Igμ chain expression, and consequent...

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4C-ing the Igh Landscape

Abstract: The assembly of antigen receptors in developing B-lymphocytes is determined by the spatio-temporal organization of the immunoglobulin heavy chain locus (Igh). In this issue of Immunity, Medvedovicet al. (2013) provide a comprehensive dynamic view of the Igh locus architecture.

Cited by 2 publications

References 10 publications

Epigenetic Regulation of Individual Modules of the immunoglobulin heavy chain locus 3â€² Regulatory Region

Epigenetic Regulation of Individual Modules of the immunoglobulin heavy chain locus 3â€² Regulatory Region

Sequential activation and distinct functions for distal and proximal modules within the IgH 3′ regulatory region

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