B cell-specific and stimulation-responsive enhancers derepress Aicda by overcoming the effects of silencers.
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-kappaB. 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.
Tran
Thinh Huy
TH
Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. honjo@mfour.med.kyoto-u.ac.jp
Nakata
Mikiyo
M
Suzuki
Keiichiro
K
Begum
Nasim A
NA
Shinkura
Reiko
R
Fagarasan
Sidonia
S
Honjo
Tasuku
T
Nagaoka
Hitoshi
H
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D003564:Cytidine Deaminase / Q000235:genetics* / Q000276:immunology; D004742:Enhancer Elements, Genetic / Q000235:genetics* / Q000276:immunology; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D005803:Genes, Immunoglobulin / Q000235:genetics* / Q000276:immunology; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D037941:Silencer Elements, Transcriptional / Q000235:genetics* / Q000276:immunology; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase