title: Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences.
abstract: Somatic hypermutation (SH) generates point mutations within rearranged immunoglobulin (Ig) genes of activated B cells, providing genetic diversity for the affinity maturation of antibodies. SH requires the activation-induced cytidine deaminase (AID) protein and transcription of the mutation target sequence, but how the Ig gene specificity of mutations is achieved has remained elusive. We show here using a sensitive and carefully controlled assay that the Ig enhancers strongly activate SH in neighboring genes even though their stimulation of transcription is negligible. Mutations in certain E-box, NFκB, MEF2, or Ets family binding sites--known to be important for the transcriptional role of Ig enhancers--impair or abolish the activity. Full activation of SH typically requires a combination of multiple Ig enhancer and enhancer-like elements. The mechanism is evolutionarily conserved, as mammalian Ig lambda and Ig heavy chain intron enhancers efficiently stimulate hypermutation in chicken cells. Our results demonstrate a novel regulatory function for Ig enhancers, indicating that they either recruit AID or alter the accessibility of the nearby transcription units.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Buerstedde
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Jukka
authors.initials: J
authors.lastname: Alinikula
authors.affiliation: IFOM-FIRC Institute of Molecular Oncology Foundation, Milano, Italy.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arakawa
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: McDonald
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: David G
authors.initials: DG
authors.lastname: Schatz
mesh_terms: D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D002645:Chickens; D003564:Cytidine Deaminase / Q000235:genetics*; D024721:E-Box Elements / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D055786:Gene Knockout Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000276:immunology; D007146:Immunoglobulin lambda-Chains / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D064326:MEF2 Transcription Factors / Q000235:genetics; D051379:Mice; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics; D016415:Sequence Alignment; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*; D014158:Transcription, Genetic; D051981:Uracil-DNA Glycosidase / Q000235:genetics; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000906:Antibodies; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D064326:MEF2 Transcription Factors; D016328:NF-kappa B; D049452:Green Fluorescent Proteins; D051981:Uracil-DNA Glycosidase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase