scholarly journals CompletecisExclusion upon Duplication of the Eμ Enhancer at the Immunoglobulin Heavy Chain Locus

2015 ◽  
Vol 35 (13) ◽  
pp. 2231-2241 ◽  
Author(s):  
Nadine Puget ◽  
Claire Leduc ◽  
Zéliha Oruc ◽  
Mohammed Moutahir ◽  
Marc Le Bert ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Critical Role ◽  
Antigen Receptor ◽  
Immunoglobulin Heavy Chain ◽  
Antisense Transcription ◽  
Regulatory Elements ◽  
Monoallelic Expression ◽  
Allelic Exclusion ◽  
Chain Locus ◽  
Heavy Chain Locus

Developing lymphocytes somatically diversify their antigen-receptor loci through V(D)J recombination. The process is associated with allelic exclusion, which results in monoallelic expression of an antigen receptor locus. Variouscis-regulatory elements control V(D)J recombination in a developmentally regulated manner, but their role in allelic exclusion is still unclear. At the immunoglobulin heavy chain locus (IgH), the Eμ enhancer plays a critical role in V(D)J recombination. We generated a mouse line with a replacement mutation in the constant region of the locus that duplicates the Eμ enhancer and allows premature expression of the γ3 heavy chain. Strikingly, IgM expression was completely and specifically excluded incisfrom the mutant allele. Thiscisexclusion recapitulated the main features of allelic exclusion, including differential exclusion of variable genes. Notably, sense and antisense transcription within the distal variable domain and distal VH-DJHrecombination were inhibited.cisexclusion was established and stably maintained despite an active endogenous Eμ enhancer. The data reveal the importance of the dynamic, developmental stage-dependent interplay betweenIgHlocus enhancers and signaling in the induction and maintenance of allelic exclusion.

scholarly journals Changes in Locus-specific V(D)J Recombinase Activity Induced by Immunoglobulin Gene Products during B Cell Development

1997 ◽  
Vol 185 (4) ◽  
pp. 609-620 ◽  
Author(s):  
Andrei Constantinescu ◽  
Mark S. Schlissel
Keyword(s):  
B Cells ◽  
B Cell ◽  
Heavy Chain ◽  
Light Chain ◽  
Immunoglobulin Heavy Chain ◽  
Cell Development ◽  
B Cell Development ◽  
Allelic Exclusion ◽  
Chain Locus ◽  
Heavy Chain Locus

The process of V(D)J recombination is crucial for regulating the development of B cells and for determining their eventual antigen specificity. Here we assess the developmental regulation of the V(D)J recombinase directly, by monitoring the double-stranded DNA breaks produced in the process of V(D)J recombination. This analysis provides a measure of recombinase activity at immunoglobulin heavy and light chain loci across defined developmental stages spanning the process of B cell development. We find that expression of a complete immunoglobulin heavy chain protein is accompanied by a drastic change in the targeting of V(D)J recombinase activity, from being predominantly active at the heavy chain locus in pro-B cells to being exclusively restricted to the light chain loci in pre-B cells. This switch in locus-specific recombinase activity results in allelic exclusion at the immunoglobulin heavy chain locus. Allelic exclusion is maintained by a different mechanism at the light chain locus. We find that immature, but not mature, B cells that already express a functional light chain protein can undergo continued light chain gene rearrangement, by replacement of the original rearrangement on the same allele. Finally, we find that the developmentally regulated targeting of V(D)J recombination is unaffected by enforced rapid transit through the cell cycle induced by an Eμ-myc transgene.

scholarly journals Allelic exclusion of the immunoglobulin heavy chain locus is independent of its nuclear localization in mature B cells

2013 ◽  
Vol 41 (14) ◽  
pp. 6905-6916 ◽  
Author(s):  
Sjoerd J. B. Holwerda ◽  
Harmen J. G. van de Werken ◽  
Claudia Ribeiro de Almeida ◽  
Ingrid M. Bergen ◽  
Marjolein J. W. de Bruijn ◽  
...  
Keyword(s):  
B Cells ◽  
Nuclear Localization ◽  
Heavy Chain ◽  
Immunoglobulin Heavy Chain ◽  
Allelic Exclusion ◽  
Chain Locus ◽  
Heavy Chain Locus

scholarly journals Inversions produced during V(D)J rearrangement at IgH, the immunoglobulin heavy-chain locus.

1995 ◽  
Vol 15 (2) ◽  
pp. 671-681 ◽  
Author(s):  
A E Sollbach ◽  
G E Wu
Keyword(s):  
Heavy Chain ◽  
Adult Mouse ◽  
Fetal Liver ◽  
Immunoglobulin Heavy Chain ◽  
Antigen Receptors ◽  
Adult Mice ◽  
Chain Locus ◽  
Heavy Chain Locus ◽  
Fetal Liver Cells

Diversity in immunoglobulin antigen receptors is generated in part by V(D)J recombination. In this process, different combinations of gene elements are joined in various configurations. Products of V(D)J recombination are coding joints, signal joints, and hybrid junctions, which are generated by deletion or inversion. To determine their role in the generation of diversity, we have examined two sorts of recombination products, coding joints and hybrid junctions, that have formed by inversion at the mouse immunoglobulin heavy-chain locus. We developed a PCR assay for quantification and characterization of inverted rearrangements of DH and JH gene elements. In primary cells from adult mice, inverted DJH rearrangements are detectable but they are rare. There were approximately 1,100 to 2,200 inverted DJH coding joints and inverted DJH hybrid junctions in the marrow of one adult mouse femur. On day 16 of gestation, inverted DJH rearrangements are more abundant. There are approximately 20,000 inverted DJH coding joints and inverted DJH hybrid junctions per day 16 fetal liver. In fetal liver cells, the number of inverted DJH rearrangements remains relatively constant from day 14 to day 16 of gestation. Inverted DJH rearrangements to JH4, the most 3' JH element, are more frequently detected than inverted DJH rearrangements to other JH elements. We compare the frequencies of inverted DJH rearrangements to previously determined frequencies of uninverted DJH rearrangements (DJH rearrangements formed by deletion). We suggest that inverted DJH rearrangements are influenced by V(D)J recombination mechanistic constraints and cellular selection.

Overexpression of HOXB7 and homeobox genes characterizes multiple myeloma patients lacking the major primary immunoglobulin heavy chain locus translocations

2011 ◽  
Vol 86 (12) ◽  
pp. E64-E66 ◽  
Author(s):  
Luca Agnelli ◽  
Paola Storti ◽  
Katia Todoerti ◽  
Gabriella Sammarelli ◽  
Benedetta Dalla Palma ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Heavy Chain ◽  
Homeobox Genes ◽  
Immunoglobulin Heavy Chain ◽  
Chain Locus ◽  
Heavy Chain Locus
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