title: The proximal J kappa germline-transcript promoter facilitates receptor editing through control of ordered recombination.
abstract: V(D)J recombination creates antibody light chain diversity by joining a Vκ gene segment with one of four Jκ segments. Two Jκ germline-transcript (GT) promoters control Vκ-Jκ joining, but the mechanisms that govern Jκ choice are unclear. Here, we show in gene-targeted mice that the proximal GT promoter helps targeting rearrangements to Jκ1 by preventing premature DNA breaks at Jκ2. Consequently, cells lacking the proximal GT promoter show a biased utilization of downstream Jκ segments, resulting in a diminished potential for receptor editing. Surprisingly, the proximal--in contrast to the distal--GT promoter is transcriptionally inactive prior to Igκ recombination, indicating that its role in Jκ choice is independent of classical promoter function. Removal of the proximal GT promoter increases H3K4me3 levels at Jκ segments, suggesting that this promoter could act as a suppressor of recombination by limiting chromatin accessibility to RAG. Our findings identify the first cis-element critical for Jκ choice and demonstrate that ordered Igκ recombination facilitates receptor editing.
authors.affiliation: Division of Immunology & Pathogenesis, Department of Molecular & Cell Biology, University of California, Berkeley, California, United States of America; Division of Molecular Immunology, Nikolaus Fiebiger Center for Molecular Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Vettermann
authors.affiliation: Division of Immunology & Pathogenesis, Department of Molecular & Cell Biology, University of California, Berkeley, California, United States of America.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Timblin
authors.affiliation: Division of Immunology & Pathogenesis, Department of Molecular & Cell Biology, University of California, Berkeley, California, United States of America.
authors.forename: Vivian
authors.initials: V
authors.lastname: Lim
authors.affiliation: Division of Immunology & Pathogenesis, Department of Molecular & Cell Biology, University of California, Berkeley, California, United States of America.
authors.forename: Ernest C
authors.initials: EC
authors.lastname: Lai
authors.affiliation: Division of Immunology & Pathogenesis, Department of Molecular & Cell Biology, University of California, Berkeley, California, United States of America.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Schlissel
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D005854:Germ Cells / Q000276:immunology / Q000378:metabolism; D006657:Histones / Q000276:immunology / Q000378:metabolism; D007133:Immunoglobulin Joining Region / Q000235:genetics / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology*; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000276:immunology*; D008239:Lysine / Q000276:immunology / Q000378:metabolism; D008297:Male; D008745:Methylation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060152:V(D)J Recombination / Q000235:genetics / Q000276:immunology*
chemical_list: D006657:Histones; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D011947:Receptors, Antigen, B-Cell; D008239:Lysine