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Mol. Cell. Biol. doi:10.1128/MCB.00631-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The regulation of Il4 gene independently controlled by proximal and distal 3'enhancers in mast cells and basophils

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

^* To whom correspondence should be addressed. Email: raysolfc{at}rcai.riken.jp.

	Abstract

Mast cells and basophils are known to be a critical IL-4 source for establishing Th2 protective responses for 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 non-cording sequence-2 (CNS-2) that was a common enhancer for memory phenotype T cells, NKT cells, mast cells and basophils. Targeted deletion of CNS-2 compromised IL-4 and several Th2 cytokine productions in connective tissue type and immature-type mast cells but not in basophils. Interestingly, the proximal 3' element containing DNase I hyper-sensitive 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 essential enhancer for Il4 gene transcription in mast cell but not in basophiles. 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.