Abstract
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-1alpha 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 Caenorhabditis elegans hif-1 and vhl-1 genes encode homologs of the HIF-1alpha subunit and VHL. To understand and describe more fully 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 identified 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 extracellular 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 an HIF-1-independent pathway for hypoxia response, and this pathway regulates the expression of multiple heat shock proteins and several transcription factors.
Highlights
The human hypoxia-inducible transcription factor hypoxia-inducible factor 1 (HIF-1) is a critical regulator of cellular and systemic responses to low oxygen levels
To identify genes regulated by HIF-1 during response to hypoxia and to determine what fraction of hypoxia-induced gene expression changes is dependent upon hif-1, we conducted genomewide studies of hypoxia-induced changes in mRNA expression in wild-type, hif-1-deficient, and vhl-1-deficient C. elegans
The primary goals of these studies were to identify hypoxiainduced gene expression changes in C. elegans and to determine which of these responses to hypoxia were regulated by hif-1
Summary
The human hypoxia-inducible transcription factor HIF-1 is a critical regulator of cellular and systemic responses to low oxygen levels. These studies identified 110 hypoxia-regulated gene expression changes, 63 of which require hif-1 function. These studies demonstrate that C. elegans hif-1 regulates the majority of early transcriptional responses to hypoxia and provide clear evidence for HIF-1-independent pathways for adaptation to oxygen deprivation.
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