Abstract
Differentiation of naive T cells into mature Th2 cells is associated with the appearance of a complex pattern of DNase I hypersensitive (DH) sites within the IL-4/IL-13 cytokine gene cluster. We show here that targeted deletion of an inducible DH site, V(A), and the adjacent conserved DH site V (CNS-2) selectively compromises IL-4 gene transcription by differentiated Th2 cells and mast cells. In mast cells, the deletion abrogates IL-4 mRNA induction, an effect mimicked by deletion of the transcription factor NFAT1 (NFATc2), which binds DH site V(A). In T cells, the deletion impairs a process of response maturation, defined by progressive increases in IL-4 levels as Th2 differentiation proceeds. These results identify an essential enhancer which regulates IL-4 gene expression in two important cell lineages in vivo.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3' Flanking Region*
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Animals
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Cell Differentiation
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Cells, Cultured
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology
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Deoxyribonuclease I / chemistry
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Enhancer Elements, Genetic*
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Gene Expression Regulation
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Interleukin-13 / biosynthesis
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Interleukin-13 / genetics
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Interleukin-4 / biosynthesis
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Interleukin-4 / genetics*
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Kinetics
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Mast Cells / immunology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Multigene Family
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NFATC Transcription Factors
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Nuclear Proteins*
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RNA, Messenger / biosynthesis
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Sequence Deletion
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Th2 Cells / immunology*
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Transcription Factors / genetics
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Transcription Factors / physiology
Substances
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DNA-Binding Proteins
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Interleukin-13
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NFATC Transcription Factors
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Nfatc2 protein, mouse
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Nuclear Proteins
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RNA, Messenger
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Transcription Factors
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Interleukin-4
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Deoxyribonuclease I