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J. Biol. Chem., Vol. 282, Issue 1, 700-709, January 5, 2007

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The Human IL-13 Locus in Neonatal CD4⁺ T Cells Is Refractory to the Acquisition of a Repressive Chromatin Architecture^*

Robin B. Webster, Yelitza Rodriguez, Walt T. Klimecki, and Donata Vercelli^¶1

From the Functional Genomics Laboratory, Arizona Respiratory Center, and ^¶Department of Cell Biology, College of Medicine, University of Arizona, Tucson, Arizona 85724

The Th2 cytokine IL-13 is a major effector molecule in human allergic inflammation. Notably, IL-13 expression at birth correlates with subsequent susceptibility to atopic disease. In order to characterize the chromatin-based mechanisms that regulate IL-13 expression in human neonatal CD4⁺ T cells, we analyzed patterns of DNase I hypersensitivity and epigenetic modifications within the IL-13 locus in cord blood CD4⁺ T cells, naive or differentiated in vitro under Th1- or Th2-polarizing conditions. In naive CD4⁺ T cells, hypersensitivity associated with DNA hypomethylation was limited to the distal promoter. Unexpectedly, during both Th1 and Th2 differentiation, the locus was extensively remodeled, as revealed by the formation of numerous HS sites and decreased DNA methylation. Obvious differences in chromatin architecture were limited to the proximal promoter, where strong hypersensitivity, hypomethylation, and permissive histone modifications were found selectively in Th2 cells. In addition to revealing the locations of putative cis-regulatory elements that may be required to control IL-13 expression in neonatal CD4⁺ T cells, our results suggest that differential IL-13 expression may depend on the acquisition of a permissive chromatin architecture at the proximal promoter in Th2 cells rather than the formation of locus-wide repressive chromatin in Th1 cells.

Received for publication, October 10, 2006

^* This work was supported by National Institutes of Health Grant R01 HL66391 (to D. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed: Arizona Respiratory Center, University of Arizona Health Sciences Center, Room 2349, 1501 N. Campbell Ave., Tucson, AZ 85724. Tel.: 520-626-6387; Fax: 520-626-6623; E-mail: donata{at}arc.arizona.edu.