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J. Biol. Chem., Vol. 282, Issue 6, 3738-3746, February 9, 2007

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Functional Dissection Identifies a Conserved Noncoding Sequence-1 Core That Mediates IL13 and IL4 Transcriptional Enhancement^*

Jannine M. Strempel and Donata Vercelli^¶1

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

Conserved noncoding sequence (CNS)-1 has been shown to coordinately regulate the expression of the Th2 cytokine genes IL4, IL13, and IL5. We have used the interaction between CNS-1 and the human IL13 and IL4 promoters as a model to pursue the molecular mechanisms underlying CNS-1-dependent regulation of Th2 cytokine gene transcription. CNS-1 potently enhanced the activity of IL13 and IL4 promoter reporter vectors upon full T cell activation. Analysis of CNS-1 deletion mutants mapped enhancer activity to a short core (CNS-1-(270–337)) that contains three closely spaced cyclic AMP-responsive elements (CRE). CRE site 2 bound CRE-binding protein (CREB) and activating transcription factor (ATF)-2 in vitro and was essential for CNS-1-dependent up-regulation of IL13 transcription. Cotransfection of an IL13 reporter construct with expression vectors for wild type or mutant CREB and ATF-2 showed that CREB, but not ATF-2, regulates CNS-1 enhancer activity. Notably, chromatin immunoprecipitation analysis showed T cell activation recruits CREB and the coactivator CREB-binding protein (CBP)/p300 to the endogenous CNS-1. Moreover, CBP/p300 activity was essential for CNS-1-mediated enhancement of IL13 transcription. Collectively, these data define the region within CNS-1 responsible for enhancement of IL13 and IL4 transcription and suggest CREB/CBP-dependent mechanisms play an important role in facilitating Th2 cytokine gene expression in response to T cell receptor signaling.

Received for publication, July 12, 2006 , and in revised form, December 1, 2006.

^* This work was supported by National Institutes of Health Grant HL66391 (to D. V.) and a National Science Foundation IGERT Fellowship in Genomics (to J. M. S.). 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 Tables I–IV.

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