title: Complete cis Exclusion upon Duplication of the Eμ Enhancer at the Immunoglobulin Heavy Chain Locus.
abstract: 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. Various cis-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 in cis from the mutant allele. This cis exclusion 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 V(H)-DJ(H) recombination were inhibited. cis exclusion was established and stably maintained despite an active endogenous Eμ enhancer. The data reveal the importance of the dynamic, developmental stage-dependent interplay between IgH locus enhancers and signaling in the induction and maintenance of allelic exclusion.
authors.forename: Nadine
authors.initials: N
authors.lastname: Puget
authors.forename: Claire
authors.initials: C
authors.lastname: Leduc
authors.forename: Zéliha
authors.initials: Z
authors.lastname: Oruc
authors.forename: Mohammed
authors.initials: M
authors.lastname: Moutahir
authors.forename: Marc
authors.initials: M
authors.lastname: Le Bert
authors.forename: Ahmed Amine
authors.initials: AA
authors.lastname: Khamlichi
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D002460:Cell Line; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D050438:Genes, Immunoglobulin Heavy Chain; D056426:Genetic Loci; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007075:Immunoglobulin M / Q000235:genetics; D038041:Lymphopoiesis; D051379:Mice; D014158:Transcription, Genetic; D060152:V(D)J Recombination
chemical_list: D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M