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A critical control element for interleukin-4 memory expression in T helper lymphocytes

Item Type:Article
Title:A critical control element for interleukin-4 memory expression in T helper lymphocytes
Creators Name:Tykocinski, L.O. and Hajkova, P. and Chang, H.D. and Stamm, T. and Soezeri, O. and Loehning, M. and Hu-Li, J. and Niesner, U. and Kreher, S. and Friedrich, B. and Pannetier, C. and Gruetz, G. and Walter, J. and Paul, W.E. and Radbruch, A.
Abstract:Naive T helper (Th) lymphocytes are induced to express the il4 (interleukin-4) gene by simultaneous signaling through the T cell receptor and the interleukin (IL)-4 receptor. Upon restimulation with antigen, such preactivated Th lymphocytes can reexpress the il4 gene independent of IL-4 receptor signaling. This memory for expression of the il4 gene depends on epigenetic modification of the il4 gene locus and an increased expression of GATA-3, the key transcription factor for Th2 differentiation. Here, we have identified a phylogenetically conserved sequence, the conserved intronic regulatory element, in the first intron of the il4 gene containing a tandem GATA-3 binding site. We show that GATA-3 binds to this sequence in a position- and orientation-dependent manner, in vitro and in vivo. DNA demethylation and histone acetylation of this region occurs early and selectively in differentiating, IL-4-secreting Th2 lymphocytes. Deletion of the conserved element by replacement of the first exon and part of the first intron of the il4 gene with gfp leads to a defect in the establishment of memory for expression of IL-4, in that reexpression of IL-4 still requires costimulation by exogenous IL-4. The conserved intronic regulatory element thus links the initial epigenetic modification of the il4 gene to GATA-3 and serves as a genetic control element for memory expression of IL-4.
Keywords:Base Sequence, Binding Sites, Conserved Sequence, DNA Methylation, DNA Primers, DNA-Binding Proteins, GATA3 Transcription Factor, Gene Expression Regulation, Immunologic Memory, Inbred BALB C Mice, Interleukin-4, Introns, Nucleic Acid Sequence Homology, Polymerase Chain Reaction, Promoter Regions (Genetics), Sequence Alignment, Spleen, T-Cell Antigen Receptors, T-Lymphocytes, Helper-Inducer, Th2 Cells, Trans-Activators, Transgenic Mice, Animals, Mice
Source:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology
Page Range:28177-28185
Date:5 August 2005
Official Publication:https://doi.org/10.1074/jbc.M502038200
PubMed:View item in PubMed

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