The cytidine deaminase AID (encoded by Aicda in mice and AICDA in humans) is critical for immunoglobulin class-switch recombination (CSR) and somatic hypermutation (SHM). Here we show that AID expression was induced by the HoxC4 homeodomain transcription factor, which bound to a highly conserved HoxC4-Oct site in the Aicda or AICDA promoter. This site functioned in synergy with a conserved binding site for the transcription factors Sp1, Sp3 and NF-κB. HoxC4 was 'preferentially' expressed in germinal center B cells and was upregulated by engagement of CD40 by CD154, as well as by lipopolysaccharide and interleukin 4. HoxC4 deficiency resulted in impaired CSR and SHM because of lower AID expression and not some other putative HoxC4-dependent activity. Enforced expression of AID in Hoxc4−/− B cells fully restored CSR. Thus, HoxC4 directly activates the Aicda promoter, thereby inducing AID expression, CSR and SHM.
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We thank M.R. Capecchi and A.M. Boulet (University of Utah) for Hoxc4+/− frozen mouse sperm; T. Fielder for technical efforts; L. Khidr, L. Phan, B. Gupta, J. Feng and Y. Zhong for handling Hoxc4+/− mice; C. Murre (University of California, San Diego) for the Aicda retroviral construct, T. Honjo (Kyoto University) for CH12F3-2A cells; C.M. Snapper (Uniformed Services University of the Health Sciences) for dextran-conjugated mAb to δ-chain; Z. Yu for statistic analysis; A. Schaffer for discussions; and S. Sabet and M. Kang for technical assistance. Supported by the US National Institutes of Health (AI 045011, AI 079705 and AI 060573 to P.C.).
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Park, S., Zan, H., Pal, Z. et al. HoxC4 binds to the promoter of the cytidine deaminase AID gene to induce AID expression, class-switch DNA recombination and somatic hypermutation. Nat Immunol 10, 540–550 (2009) doi:10.1038/ni.1725
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