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HIF-1 regulates iron homeostasis in Caenorhabditis elegans by activation and inhibition of genes involved in iron uptake and storage.
- Source :
-
PLoS genetics [PLoS Genet] 2011 Dec; Vol. 7 (12), pp. e1002394. Date of Electronic Publication: 2011 Dec 15. - Publication Year :
- 2011
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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.<br />Competing Interests: The authors have declared that no competing interests exist.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7404
- Volume :
- 7
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- PLoS genetics
- Publication Type :
- Academic Journal
- Accession number :
- 22194696
- Full Text :
- https://doi.org/10.1371/journal.pgen.1002394