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J. Biol. Chem., Vol. 283, Issue 2, 716-725, January 11, 2008

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An Iron Enhancer Element in the FTN-1 Gene Directs Iron-dependent Expression in Caenorhabditis elegans Intestine^*

S. Joshua Romney, Colin Thacker, and Elizabeth A. Leibold^¶||1

From the Eccles Program in Human Molecular Biology and Genetics, the Departments of ^¶Medicine and ^||Oncological Sciences, and the Health Science Center Core Research Facilities, University of Utah, Salt Lake City, Utah 84112

Ferritin is a ubiquitous protein that sequesters iron and protects cells from iron toxicity. Caenorhabditis elegans express two ferritins, FTN-1 and FTN-2, which are transcriptionally regulated by iron. To identify the cis-acting sequences and proteins required for iron-dependent regulation of ftn-1 and ftn-2 expression, we generated transcriptional GFP reporters corresponding to 5 '-upstream sequences of the ftn-1 and ftn-2 genes. We identified a conserved 63-bp sequence, the iron-dependent element (IDE), that is required for iron-dependent regulation of a ftn-1 GFP reporter in intestine. The IDE contains two GATA-binding motifs and three octameric direct repeats. Site-directed mutagenesis of the GATA sequences, singly or in combination, reduces ftn-1 GFP reporter expression in the intestine. In vitro DNA mobility shift assays show that the intestine-specific GATA protein ELT-2 binds to both GATA sequences. Inhibition of ELT-2 function by RNA interference blocks ftn-1 GFP reporter expression in vivo. Insertion of the IDE into the promoter region of a heterologous reporter activates iron-dependent transcription in intestine. These data demonstrate that the activation of ftn-1 and ftn-2 transcription by iron requires ELT-2 and that the IDE functions as an iron-dependent enhancer in intestine.

Received for publication, August 22, 2007 , and in revised form, October 17, 2007.

^* This work was supported by National Institutes of Health Grants R01GMS45201 and R01DK068602 (to E. A. L.) and a Center of Excellence Grant in Hematology 1P30DK072437. 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. S1 and S2.

¹ To whom correspondence should be addressed: University of Utah, 15 N. 2030 E., Rm. 3240, Salt Lake City, UT 84112. Tel.: 801-585-5002; Fax: 801-585-3501; E-mail: betty.leibold{at}hmbg.utah.edu.

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