Regulation of the Il4 gene is independently controlled by proximal and distal 3' enhancers in mast cells and basophils.
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.
Yagi
Ryouji
R
Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Suehiro-cho 1-7-22, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
Tanaka
Shinya
S
Motomura
Yasutaka
Y
Kubo
Masato
M
D000818:Animals; D001491:Basophils / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D018793:Interleukin-13 / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics*; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D010537:Peritoneum / Q000166:cytology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D017384:Sequence Deletion; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism
D006657:Histones; D018793:Interleukin-13; D049452:Green Fluorescent Proteins; D015847:Interleukin-4; D019009:Proto-Oncogene Proteins c-kit