The human hypoxia inducible transcription factor HIF-1 is a critical regulator of cellular and systemic responses to low oxygen levels. When oxygen levels are high, the HIF-1 alpha subunit is hydroxylated and is targeted for degradation by the von Hippel-Lindau tumor suppressor protein (VHL). This regulatory pathway is evolutionarily conserved, and the C. elegans
hif-1 and
vhl-1 genes encode homologs of the HIF alpha subunit and VHL. To more fully understand and describe the molecular basis for hypoxia response in this important genetic model system, we compared hypoxia-induced changes in mRNA expression in wild-type,
hif-1-deficient, and
vhl-1-deficient C. elegans using whole-genome microarrays. These studies identify 110 hypoxia-regulated gene expression changes, 63 of which require
hif-1 function. Mutation of
vhl-1 abrogates most
hif-1-dependent changes in mRNA expression. Genes regulated by C. elegans
hif-1 have predicted functions in signal transduction, metabolism, transport, and extra cellular matrix remodeling. We examined the in vivo requirement for 16 HIF-1 target genes and discovered that the
phy-2 prolyl 4-hydroxylase alpha subunit is critical for survival in hypoxic conditions. Some HIF-1 target genes negatively regulate formation of stress-resistant dauer larvae. The microarray data presented herein also provide clear evidence for a HIF-1-independent pathway for hypoxia response, and this pathway regulates the expression of multiple heat shock proteins and several transcription factors.