title: Induction of activation-induced cytidine deaminase-targeting adaptor 14-3-3γ is mediated by NF-κB-dependent recruitment of CFP1 to the 5'-CpG-3'-rich 14-3-3γ promoter and is sustained by E2A.
abstract: Class switch DNA recombination (CSR) crucially diversifies Ab biologic effector functions. 14-3-3γ specifically binds to the 5'-AGCT-3' repeats in the IgH locus switch (S) regions. By interacting directly with the C-terminal region of activation-induced cytidine deaminase (AID), 14-3-3γ targets this enzyme to S regions to mediate CSR. In this study, we showed that 14-3-3γ was expressed in germinal center B cells in vivo and induced in B cells by T-dependent and T-independent primary CSR-inducing stimuli in vitro in humans and mice. Induction of 14-3-3γ was rapid, peaking within 3 h of stimulation by LPSs, and sustained over the course of AID and CSR induction. It was dependent on recruitment of NF-κB to the 14-3-3γ gene promoter. The NF-κB recruitment enhanced the occupancy of the CpG island within the 14-3-3γ promoter by CFP1, a component of the COMPASS histone methyltransferase complex, and promoter-specific enrichment of histone 3 lysine 4 trimethylation (H3K4me3), which is indicative of open chromatin state and marks transcription-competent promoters. NF-κB also potentiated the binding of B cell lineage-specific factor E2A to an E-box motif located immediately downstream of the two closely-spaced transcription start sites for sustained 14-3-3γ expression and CSR induction. Thus, 14-3-3γ induction in CSR is enabled by the CFP1-mediated H3K4me3 enrichment in the promoter, dependent on NF-κB and sustained by E2A.
authors.affiliation: Institute for Immunology, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Thach
authors.initials: T
authors.lastname: Mai
authors.forename: Egest J
authors.initials: EJ
authors.lastname: Pone
authors.forename: Guideng
authors.initials: G
authors.lastname: Li
authors.forename: Tonika S
authors.initials: TS
authors.lastname: Lam
authors.forename: J'aime
authors.initials: J
authors.lastname: Moehlman
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Xu
authors.forename: Paolo
authors.initials: P
authors.lastname: Casali
mesh_terms: D048948:14-3-3 Proteins / Q000096:biosynthesis* / Q000235:genetics; D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002478:Cells, Cultured; D017124:Conserved Sequence; D018899:CpG Islands / Q000235:genetics*; D003564:Cytidine Deaminase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D024721:E-Box Elements / Q000235:genetics; D018858:Germinal Center / Q000378:metabolism; D057809:HEK293 Cells; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000502:physiology*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008211:Lymphocyte Cooperation; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011499:Protein Processing, Post-Translational; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D013047:Specific Pathogen-Free Organisms; D015534:Trans-Activators / Q000502:physiology*; D024363:Transcription Initiation Site; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D048948:14-3-3 Proteins; D020413:3' Untranslated Regions; D051792:Basic Helix-Loop-Helix Proteins; D003564:Cytidine Deaminase; D004268:DNA-Binding Proteins; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D008070:Lipopolysaccharides; D016328:NF-kappa B; D015534:Trans-Activators; D000098830:AICDA (Activation-Induced Cytidine Deaminase); C409062:CXXC1 protein, human; C501971:Cxxc1 protein, mouse; C407909:TCF3 protein, human; C075668:Tcf3 protein, mouse; C482199:lipopolysaccharide, E coli O55-B5