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B cell–specific and stimulation-responsive enhancers derepress Aicda by overcoming the effects of silencers

Nature Immunology volume 11, pages 148–154 (2010)Cite this article

Abstract

Activation-induced cytidine deaminase (AID) is essential for the generation of antibody memory but also targets oncogenes, among other genes. We investigated the transcriptional regulation of Aicda (which encodes AID) in class switch–inducible CH12F3-2 cells and found that Aicda regulation involved derepression by several layers of positive regulatory elements in addition to the 5′ promoter region. The 5′ upstream region contained functional motifs for the response to signaling by cytokines, the ligand for the costimulatory molecule CD40 or stimuli that activated the transcription factor NF-κB. The first intron contained functional binding elements for the ubiquitous silencers c-Myb and E2f and for the B cell–specific activator Pax5 and E-box-binding proteins. Our results show that Aicda is regulated by the balance between B cell–specific and stimulation-responsive elements and ubiquitous silencers.

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Figure 1: General characterization of Aicda regions 1–4 by luciferase reporter assay.
Figure 2: Region 2 contains both enhancer and suppressor elements.
Figure 3: Analysis of CIT-responsive elements in region 4.
Figure 4: Elements in region 4 that are responsive to the CIT stimulation.
Figure 5: Roles of the Pax5 motif and the E-box in region 2 in B cells.
Figure 6: ChIP assay of the in vivo binding of transcription factors.
Figure 7: Time-course analysis of the expression of candidate transcription factors that may interact with Aicda regulatory regions.

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Acknowledgements

We thank I. Taniuchi for critical comments and Y. Shiraki and T. Kanda for help in the preparation of the manuscript. Supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant-in-Aid for Specially Promoted Research 17002015).

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Authors and Affiliations

  1. Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Thinh Huy Tran, Mikiyo Nakata, Nasim A Begum, Reiko Shinkura, Tasuku Honjo & Hitoshi Nagaoka

  2. Laboratory for Mucosal Immunity, RIKEN, Yokohama, Japan

    Thinh Huy Tran, Keiichiro Suzuki & Sidonia Fagarasan

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  1. Thinh Huy Tran
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Contributions

T.H.T., T.H. and H.N. designed the study; T.H.T., M.N., K.S. and H.N. did experiments; N.A.B., R.S. and S.F. provided reagents and suggestions and T.H.T., T.H. and H.N. wrote the manuscript.

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Correspondence to Tasuku Honjo.

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Tran, T., Nakata, M., Suzuki, K. et al. B cell–specific and stimulation-responsive enhancers derepress Aicda by overcoming the effects of silencers. Nat Immunol 11, 148–154 (2010). https://doi.org/10.1038/ni.1829

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