Dataset Information

Epigenetic Regulation of Individual Modules of the immunoglobulin heavy chain locus 3' Regulatory Region.

ABSTRACT: 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 C? 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 C?, 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.

SUBMITTER: Birshtein BK

PROVIDER: S-EPMC4000994 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Epigenetic Regulation of Individual Modules of the immunoglobulin heavy chain locus 3' Regulatory Region.

Birshtein Barbara K BK

Frontiers in immunology 20140421

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 us ...[more]

PMID: 24795714

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Project description:The immunoglobulin heavy chain locus undergoes a series of DNA rearrangements and modifications to achieve the construction and expression of individual antibody heavy chain genes in B cells. These events affect variable regions, through VDJ joining and subsequent somatic hypermutation, and constant regions through class switch recombination (CSR). Levels of IgH expression are also regulated during B cell development, resulting in high levels of secreted antibodies from fully differentiated plasma cells. Regulation of these events has been attributed primarily to two cis-elements that work from long distances on their target sequences, i.e., an ∼1 kb intronic enhancer, Eμ, located between the V region segments and the most 5' constant region gene, Cμ; and an ∼40 kb 3' regulatory region (3' RR) that is located downstream of the most 3' C(H) gene, Cα. The 3' RR is a candidate for an "end" of B cell-specific regulation of the Igh locus. The 3' RR contains several B cell-specific enhancers associated with DNase I hypersensitive sites (hs1-4), which are essential for CSR and for high levels of IgH expression in plasma cells. Downstream of this enhancer-containing region is a region of high-density CTCF binding sites, which extends through hs5, 6, and 7 and further downstream. CTCF, with its enhancer-blocking activities, has been associated with all mammalian insulators and implicated in multiple chromosomal interactions. Here we address the 3' RR CTCF-binding region as a potential insulator of the Igh locus, an independent regulatory element and a predicted modulator of the activity of 3' RR enhancers. Using chromosome conformation capture technology, chromatin immunoprecipitation, and genetic approaches, we have found that the 3' RR with its CTCF-binding region interacts with target sequences in the V(H), Eμ, and C(H) regions through DNA looping as regulated by protein binding. This region impacts on B cell-specific Igh processes at different stages of B cell development.

Dataset Information

Epigenetic Regulation of Individual Modules of the immunoglobulin heavy chain locus 3' Regulatory Region.

Publications

Epigenetic Regulation of Individual Modules of the immunoglobulin heavy chain locus 3' Regulatory Region.

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