HIF-1 regulates iron homeostasis in caenorhabditis elegans by activation and inhibition of genes involved in iron uptake and storage

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. © 2011 romney et al.