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Regulation of the Il4 Gene Is Independently Controlled by Proximal and Distal 3' Enhancers in Mast Cells and Basophils

Ryouji Yagi,^1, Shinya Tanaka,^1,2, Yasutaka Motomura,^1,2 and Masato Kubo^1*

Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Suehiro-cho 1-7-22, Tsurumi, Yokohama, Kanagawa 230-0045, Japan,¹ Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda City, Chiba 278-0022, Japan²

Received 11 April 2007/ Returned for modification 31 August 2007/ Accepted 19 September 2007

Mast cells and basophils are known to be a critical interleukin 4 (IL-4) source for establishing Th2 protective responses to parasitic infections. Chromatin structure and histone modification patterns in the Il13/Il4 locus of mast cells were similar to those of IL-4-producing type 2 helper T cells. However, using a transgenic approach, we found that Il4 gene expression was distinctly regulated by individual cis regulatory elements in cell types of different lineages. The distal 3' element contained conserved noncoding sequence 2 (CNS-2), which was a common enhancer for memory phenotype T cells, NKT cells, mast cells, and basophils. Targeted deletion of CNS-2 compromised production of IL-4 and several Th2 cytokines in connective-tissue-type and immature-type mast cells but not in basophils. Interestingly, the proximal 3' element containing DNase I-hypersensitive site 4 (HS4), which controls Il4 gene silencing in T-lineage cells, exhibited selective enhancer activity in basophils. These results indicate that CNS-2 is an essential enhancer for Il4 gene transcription in mast cell but not in basophils. The transcription of the Il4 gene in mast cells and basophils is independently regulated by CNS-2 and HS4 elements that may be critical for lineage-specific Il4 gene regulation in these cell types.

Published ahead of print on 1 October 2007.

R. Yagi and S. Tanaka contributed equally to this work.