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Papers In Press, published online ahead of print June 7, 2005
J. Biol. Chem, 10.1074/jbc.M502038200
Submitted on February 23, 2005
Revised on May 18, 2005
Accepted on June 7, 2005
German Arthritis Research Centre Berlin, Berlin 10117
Corresponding Author: tykocinski{at}drfz.de
Naïve T helper (Th) lymphocytes are induced to express the interleukin-4 (il4) gene by simultaneous signaling through the T cell receptor (TcR) and the 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 (conserved intronic regulatory element, CIRE) 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 CIRE 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.
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