Sequential activation and distinct functions for distal and proximal modules within the IgH 3′ regulatory region

• Published in: Proceedings of the National Academy of Sciences - PNAS 2016-02, Vol.113 (6), p.1618-1623
• Main Authors: Garot, Armand, Marquet, Marie, Saintamand, Alexis, Bender, Sébastien, Le Noir, Sandrine, Rouaud, Pauline, Carrion, Claire, Oruc, Zéliha, Bébin, Anne-Gaëlle, Moreau, Jeanne, Lebrigand, Kevin, Denizot, Yves, Alt, Frederick W., Cogné, Michel, Pinaud, Eric
• Format: Article
• Language: English
• Subjects: Animals; Antibody Formation; Antigens - metabolism; B-Lymphocytes - metabolism; Biological Sciences; Cell Count; Cell Lineage; Cells; Flow Cytometry; Gene Targeting; Germinal Center - metabolism; Heterozygote; Immunoglobulin Class Switching - genetics; Immunoglobulin Heavy Chains - genetics; Immunoglobulin M - metabolism; Immunoglobulins; Immunology; Life Sciences; Mice, Inbred C57BL; Mice, Knockout; Plasma; Proteins; Receptors, Antigen, B-Cell - metabolism; Regulatory Sequences, Nucleic Acid - genetics; RNA, Antisense - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Sequence Deletion; Somatic Hypermutation, Immunoglobulin - genetics; Transcription factors; Transcription, Genetic
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1514090113

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.