1. HIF-1 regulates iron homeostasis in Caenorhabditis elegans by activation and inhibition of genes involved in iron uptake and storage.
- Author
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Romney SJ, Newman BS, Thacker C, and Leibold EA
- Subjects
- Animals, Binding Sites, Caenorhabditis elegans Proteins genetics, Cation Transport Proteins genetics, Cation Transport Proteins metabolism, Ferritins genetics, GATA Transcription Factors genetics, GATA Transcription Factors metabolism, Homeostasis genetics, Intestinal Mucosa metabolism, Iron Deficiencies, Protein Binding, RNA Interference, Transcription Factors genetics, Transcriptional Activation, Caenorhabditis elegans genetics, Caenorhabditis elegans growth & development, Caenorhabditis elegans Proteins metabolism, Gene Expression Regulation, Developmental, Iron metabolism, Transcription Factors metabolism
- Abstract
Caenorhabditis elegans ftn-1 and ftn-2, which encode the iron-storage protein ferritin, are transcriptionally inhibited during iron deficiency in intestine. Intestinal specific transcription is dependent on binding of ELT-2 to GATA binding sites in an iron-dependent enhancer (IDE) located in ftn-1 and ftn-2 promoters, but the mechanism for iron regulation is unknown. Here, we identify HIF-1 (hypoxia-inducible factor -1) as a negative regulator of ferritin transcription. HIF-1 binds to hypoxia-response elements (HREs) in the IDE in vitro and in vivo. Depletion of hif-1 by RNA interference blocks transcriptional inhibition of ftn-1 and ftn-2 reporters, and ftn-1 and ftn-2 mRNAs are not regulated in a hif-1 null strain during iron deficiency. An IDE is also present in smf-3 encoding a protein homologous to mammalian divalent metal transporter-1. Unlike the ftn-1 IDE, the smf-3 IDE is required for HIF-1-dependent transcriptional activation of smf-3 during iron deficiency. We show that hif-1 null worms grown under iron limiting conditions are developmentally delayed and that depletion of FTN-1 and FTN-2 rescues this phenotype. These data show that HIF-1 regulates intestinal iron homeostasis during iron deficiency by activating and inhibiting genes involved in iron uptake and storage., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2011
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