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

Abstract

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.

We are grateful to H. Fujimoto, Y. Matsuno, Y. Suzuki, and M. Nakamura for technical assistance.

This work was supported by grants from the Grants in Aid for Scientific Research (B) and Grants in Aid for Scientific Research on Priority Areas programs of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan. Yasutaka Motomura is the recipient of a Junior Research Associate grant at RIKEN. S. Tanaka is a recipient of the Special Postdoctoral Researchers program at RIKEN.