title: Sequential activation and distinct functions for distal and proximal modules within the IgH 3' regulatory region.
abstract: As a master regulator of functional Ig heavy chain (IgH) expression, the IgH 3' regulatory region (3'RR) controls multiple transcription events at various stages of B-cell ontogeny, from newly formed B cells until the ultimate plasma cell stage. The IgH 3'RR plays a pivotal role in early B-cell receptor expression, germ-line transcription preceding class switch recombination, interactions between targeted switch (S) regions, variable region transcription before somatic hypermutation, and antibody heavy chain production, but the functional ranking of its different elements is still inaccurate, especially that of its evolutionarily conserved quasi-palindromic structure. By comparing relevant previous knockout (KO) mouse models (3'RR KO and hs3b-4 KO) to a novel mutant devoid of the 3'RR quasi-palindromic region (3'PAL KO), we pinpointed common features and differences that specify two distinct regulatory entities acting sequentially during B-cell ontogeny. Independently of exogenous antigens, the 3'RR distal part, including hs4, fine-tuned B-cell receptor expression in newly formed and naïve B-cell subsets. At mature stages, the 3'RR portion including the quasi-palindrome dictated antigen-dependent locus remodeling (global somatic hypermutation and class switch recombination to major isotypes) in activated B cells and antibody production in plasma cells.
authors.affiliation: Contrôle de la Réponse Immune B et des Lymphoproliférations, UMR 7276, Centre National de la Recherche Scientifique, Université de Limoges, 87025 Limoges, France;
authors.forename: Armand
authors.initials: A
authors.lastname: Garot
authors.affiliation: Contrôle de la Réponse Immune B et des Lymphoproliférations, UMR 7276, Centre National de la Recherche Scientifique, Université de Limoges, 87025 Limoges, France; Service de Néphrologie, Centre Hospitalier Universitaire Dupuytren, F-87042 Limoges, France;
authors.forename: Marie
authors.initials: M
authors.lastname: Marquet
authors.affiliation: Contrôle de la Réponse Immune B et des Lymphoproliférations, UMR 7276, Centre National de la Recherche Scientifique, Université de Limoges, 87025 Limoges, France;
authors.forename: Alexis
authors.initials: A
authors.lastname: Saintamand
authors.affiliation: Contrôle de la Réponse Immune B et des Lymphoproliférations, UMR 7276, Centre National de la Recherche Scientifique, Université de Limoges, 87025 Limoges, France; Centre de Référence des Amyloses, Centre Hospitalier Universitaire Dupuytren, F-87042 Limoges, France;
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bender
authors.affiliation: Contrôle de la Réponse Immune B et des Lymphoproliférations, UMR 7276, Centre National de la Recherche Scientifique, Université de Limoges, 87025 Limoges, France;
authors.forename: Sandrine
authors.initials: S
authors.lastname: Le Noir
authors.affiliation: Contrôle de la Réponse Immune B et des Lymphoproliférations, UMR 7276, Centre National de la Recherche Scientifique, Université de Limoges, 87025 Limoges, France;
authors.forename: Pauline
authors.initials: P
authors.lastname: Rouaud
authors.affiliation: Contrôle de la Réponse Immune B et des Lymphoproliférations, UMR 7276, Centre National de la Recherche Scientifique, Université de Limoges, 87025 Limoges, France;
authors.forename: Claire
authors.initials: C
authors.lastname: Carrion
authors.affiliation: Contrôle de la Réponse Immune B et des Lymphoproliférations, UMR 7276, Centre National de la Recherche Scientifique, Université de Limoges, 87025 Limoges, France;
authors.forename: Zéliha
authors.initials: Z
authors.lastname: Oruc
authors.affiliation: Contrôle de la Réponse Immune B et des Lymphoproliférations, UMR 7276, Centre National de la Recherche Scientifique, Université de Limoges, 87025 Limoges, France;
authors.forename: Anne-Gaëlle
authors.initials: AG
authors.lastname: Bébin
authors.affiliation: Contrôle de la Réponse Immune B et des Lymphoproliférations, UMR 7276, Centre National de la Recherche Scientifique, Université de Limoges, 87025 Limoges, France;
authors.forename: Jeanne
authors.initials: J
authors.lastname: Moreau
authors.affiliation: Université Nice Sophia Antipolis, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne Sophia-Antipolis, France;
authors.forename: Kevin
authors.initials: K
authors.lastname: Lebrigand
authors.affiliation: Contrôle de la Réponse Immune B et des Lymphoproliférations, UMR 7276, Centre National de la Recherche Scientifique, Université de Limoges, 87025 Limoges, France;
authors.forename: Yves
authors.initials: Y
authors.lastname: Denizot
authors.affiliation: Program in Cellular and Molecular Medicine, Howard Hughes Medical Institute, Boston, MA 02115; Department of Genetics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.affiliation: Contrôle de la Réponse Immune B et des Lymphoproliférations, UMR 7276, Centre National de la Recherche Scientifique, Université de Limoges, 87025 Limoges, France; Institut Universitaire de France, Université de Limoges, 87000 Limoges, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Cogné
authors.affiliation: Contrôle de la Réponse Immune B et des Lymphoproliférations, UMR 7276, Centre National de la Recherche Scientifique, Université de Limoges, 87025 Limoges, France; eric.pinaud@unilim.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Pinaud
mesh_terms: D000818:Animals; D000917:Antibody Formation; D000941:Antigens / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D002452:Cell Count; D019070:Cell Lineage; D005434:Flow Cytometry; D018390:Gene Targeting; D018858:Germinal Center / Q000378:metabolism; D006579:Heterozygote; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007075:Immunoglobulin M / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016372:RNA, Antisense / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D017384:Sequence Deletion; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D000941:Antigens; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D016372:RNA, Antisense; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell
keywords: B-cell development; enhancers; immunoglobulin gene regulation
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