The immunoglobulin IGHD gene locus in C57BL/6 mice

In addition to producing conventional tetrameric IgGs, camelids have the particularity of producing a functional homodimeric IgG type lacking L (light) chains and only made up of two H (heavy) chains. This nonconventional IgG type is characterized by variable and constant regions referred to as VHH and CHH, respectively, and which differ from conventional VH and CH counterparts. Although the structural properties of homodimeric IgGs have been well investigated, the genetic bases involved in their generation are still largely unknown. In this study, we characterized the organization of genes coding for the H chains of tetrameric and homodimeric IgGs by constructing an alpaca (Lama pacos) genomic cosmid library. We showed that a single IgH locus in alpaca chromosome 4 contains all of the genetic elements required for the generation of the two types of Igs. The alpaca IgH locus is composed of a V region that contains both VHH and VH genes followed by a unique DH-JH cluster and C region genes, which include both CHH and CH genes. Although this general gene organization greatly resembles that of other typical mammalian Vn-Dn-Jn-Cn translocon IgH loci, the intermixed gene organization within the alpaca V and C regions reveals a new type of translocon IgH locus. Furthermore, analyses of cDNA coding for the membrane forms of IgG and IgM present in alpaca peripheral blood B cells are most consistent with the notion that the development of a B cell bearing homodimeric IgG passes through an IgM+ stage, similar to the case for conventional IgG.

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“…1). Reminiscent of other mammalian IgH loci (i.e., human and mouse) (16,17), the D H 7 gene is clustered together with the J H gene.…”

Section: H -J H Clustermentioning

confidence: 99%

Tetrameric and Homodimeric Camelid IgGs Originate from the Same IgH Locus

Achour

Cavelier

Tichit

et al. 2008

The Journal of Immunology

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“…1A). Nucleotide Identity X analysis shows that it contains one previously reported D H gene (DST4.2), which has never undergone D to J recombination (27), and Myef2rpg (myelin basic expression factor 2 repressor pseudogene) (GenBank TM accession number XM_621300). Most notably, the V-D region encodes two genes, Adam6a and Adam6b (a distintegrin and metalloproteinase domain 6a and -b) (31).…”

Section: Mice Cell Lines and Cell Sorting-rag1mentioning

confidence: 99%

“…The sequence of the mouse region was established through bacterial artificial chromosome assembly using Sequencher (Gene Codes): RP23-109B20, RP24-275L15, RP23-404D8, and RP23-270B12 (the last two cover the Igh D region) (27). These bacterial artificial chromosomes provide at least 2-fold coverage except in four regions of 12,735, 1087, 528, and 430 bp, which have single strand coverage.…”

Section: Mice Cell Lines and Cell Sorting-rag1mentioning

confidence: 99%

The Mouse Immunoglobulin Heavy Chain V-D Intergenic Sequence Contains Insulators That May Regulate Ordered V(D)J Recombination

Featherstone¹,

Wood²,

Bowen³

et al. 2010

Journal of Biological Chemistry

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V(D)J recombination of the multigene antigen receptor loci is essential for the generation of a diverse antigen receptor repertoire. Recombination is strictly regulated, occurring only in lymphocytes due to restricted expression of the recombination activating gene enzymes, RAG1 and RAG2, therein. Further, T cell receptors only recombine in T cells, B cell receptors only recombine in B cells, and the loci only recombine at specific stages in lymphocyte differentiation. In B cells, the Igh recombines before the Ig light chains. Finally some antigen receptor loci (e.g. the Igh) have two ordered recombination events. A D gene first recombines with a J gene on both alleles, followed by recombination of a V gene to the DJ recombined segment. Once a productive VDJ rearrangement has been generated, further V to DJ recombination is prevented on the second allele, a process termed allelic exclusion, which in B cells ensures that each B cell expresses a monoclonal IgH (1).Ordered recombination is crucial for antigen receptor integrity, but key questions remain: how is recombination order achieved, and how is it regulated? Numerous studies have suggested that order is achieved through alterations in the chromatin conformation of individual gene domains at sequential stages of lymphocyte development (2). In the mouse Igh locus, the D-J-C region acquires histone post-translational modifications characteristic of open chromatin before the V region (3, 4). Non-coding RNA transcripts, including I, generated from E, located 3Ј of the J genes (5), and o, transcribed from the promoter of the most 3Ј D gene, DQ52, occur on germ line alleles (6). Following D to J recombination, non-coding transcripts are generated from the V genes (7,8). Furthermore, extensive antisense intergenic transcription occurs throughout the D and J domains before D to J, and then throughout the V domain before V to DJ recombination (9, 10). Nuclear positioning may also play a role in ordered V(D)J recombination. The Igh locus is tethered at the nuclear periphery via the V region in non-B cells (11,12). Relocation toward euchromatic regions occurs preferentially from the DJC end, favoring D to J recombination. Furthermore, locus compaction through DNA looping is required for distal V gene recombination (13,14). Several transcription factors, including Pax5 (13), YY1 (15), and Ikaros (16), play a role in looping, and in their absence, only the D-proximal V genes recombine. Following productive V(D)J recombination and cell surface expression of an IgH polypeptide, several of the above processes are reversed to silence V to DJ recombination of the second allele by allelic exclusion. Both Igh V regions decontract, V region germ line transcription is lost, and the second Igh allele is recruited to pericentric heterochromatin via the D-distal V genes (1). In contrast, both DJC regions remain transcriptionally active (9, 17). Thus, there is differential chromatin regulation of both activation and inactivation of the DJC versus V regions of the Igh locus.

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“…These V H gene families are partially interspersed with one another but, depending on position, can be divided into proximal (3′ part of the V H cluster, close to IgH-D region, for example, V H 7183), intermediate (e.g., V H S107), and distal (5′ part of the V H cluster, distant from IgH-D region, for example, V H J558) families. 3′ of the V H elements, separated by ~90 kb, lie 10-15 D segments (Retter et al, 2007;Ye, 2004) followed by 4 J H elements. Because to the uniform transcriptional orientation of V, D, and J segments, V(D)J recombination events at the IgH locus result in deletion of the intervening sequence.…”

Section: The Immunoglobulin Heavy Chain Locusmentioning

confidence: 99%

Chapter 1 Cis‐Regulatory Elements and Epigenetic Changes Control Genomic Rearrangements of the IgH Locus

Perlot

Alt

2008

Advances in Immunology

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Immunoglobulin variable region exons are assembled from discontinuous variable (V), diversity (D), and joining (J) segments by the process of V(D)J recombination. V(D)J rearrangements of the immunoglobulin heavy chain (IgH) locus are tightly controlled in a tissue-specific, ordered and allele-specific manner by regulating accessibility of V, D, and J segments to the recombination activating gene proteins which are the specific components of the V(D)J recombinase. In this review we discuss recent advances and established models brought forward to explain the mechanisms underlying accessibility control of V(D)J recombination, including research on germline transcripts, spatial organization, and chromatin modifications of the immunoglobulin heavy chain (IgH) locus. Furthermore, we review the functions of well-described and potential new cis-regulatory elements with regard to processes such as V(D)J recombination, allelic exclusion, and IgH class switch recombination.

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The immunoglobulin IGHD gene locus in C57BL/6 mice

Cited by 24 publications

References 27 publications

Tetrameric and Homodimeric Camelid IgGs Originate from the Same IgH Locus

Tetrameric and Homodimeric Camelid IgGs Originate from the Same IgH Locus

The Mouse Immunoglobulin Heavy Chain V-D Intergenic Sequence Contains Insulators That May Regulate Ordered V(D)J Recombination

Chapter 1 Cis‐Regulatory Elements and Epigenetic Changes Control Genomic Rearrangements of the IgH Locus

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