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

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