title: In vivo redundant function of the 3' IgH regulatory element HS3b in the mouse.
abstract: In the mouse, the regulatory region located at the 3' end of the IgH locus includes four transcriptional enhancers: HS3a, HS1-2, HS3b, and HS4; the first three lie in a quasi-palindromic structure. Although the upstream elements HS3a and HS1-2 proved dispensable for Ig expression and class switch recombination (CSR), the joint deletion of HS3b and HS4 led to a consistent decrease in IgH expression in resting B cells and to a major CSR defect. Within this pair of distal enhancers, it was questionable whether HS3b and HS4 could be considered individually as elements critical for IgH expression and/or CSR. Studies in HS4-deficient mice recently revealed the role of HS4 as restricted to Igmicro-chain expression from the pre-B to the mature B cell stage and left HS3b as the last candidate for CSR regulation. Our present study finally invalidates the hypothesis that CSR could mostly rely on HS3b itself. B cells from HS3b-deficient animals undergo normal proliferation, germline transcription, and CSR upon in vitro stimulation with LPS; in vivo Ag-specific responses are not affected. In conclusion, our study highlights a major effect of the global ambiance of the IgH locus; enhancers demonstrated as being strongly synergistic in transgenes turn out to be redundant in their endogenous context.
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche, Université de Limoges, Limoges, France.
authors.forename: Anne-Gaëlle
authors.initials: AG
authors.lastname: Bébin
authors.forename: Claire
authors.initials: C
authors.lastname: Carrion
authors.forename: Marie
authors.initials: M
authors.lastname: Marquet
authors.forename: Nadine
authors.initials: N
authors.lastname: Cogné
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lecardeur
authors.forename: Michel
authors.initials: M
authors.lastname: Cogné
authors.forename: Eric
authors.initials: E
authors.lastname: Pinaud
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics / Q000276:immunology; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D015139:Blotting, Southern; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics* / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D050436:Regulatory Elements, Transcriptional / Q000235:genetics* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020413:3' Untranslated Regions; D007143:Immunoglobulin Heavy Chains