Induction of activation-induced cytidine deaminase-targeting adaptor 14-3-3? is mediated by NF-?B-dependent recruitment of CFP1 to the 5'-CpG-3'-rich 14-3-3? promoter and is sustained by E2A.

ABSTRACT: Class switch DNA recombination (CSR) crucially diversifies Ab biologic effector functions. 14-3-3? 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), 14-3-3? targets this enzyme to S regions to mediate CSR. In this study, we showed that 14-3-3? 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 14-3-3? 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-?B to the 14-3-3? gene promoter. The NF-?B recruitment enhanced the occupancy of the CpG island within the 14-3-3? 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-?B 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 14-3-3? expression and CSR induction. Thus, 14-3-3? induction in CSR is enabled by the CFP1-mediated H3K4me3 enrichment in the promoter, dependent on NF-?B and sustained by E2A.

SUBMITTER: Mai T 

PROVIDER: S-EPMC3833273 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature