Abstract
Hypoxia-inducible factors (HIFs) are a family of evolutionary conserved alpha-beta heterodimeric transcription factors that induce a wide range of genes in response to low oxygen tension. Molecular mechanisms that mediate oxygen-dependent HIF regulation operate at the level of the alpha subunit, controlling protein stability, subcellular localization, and transcriptional coactivator recruitment. We have conducted an unbiased genome-wide RNA interference (RNAi) screen in Drosophila cells aimed to the identification of genes required for HIF activity. After 3 rounds of selection, 30 genes emerged as critical HIF regulators in hypoxia, most of which had not been previously associated with HIF biology. The list of genes includes components of chromatin remodeling complexes, transcription elongation factors, and translational regulators. One remarkable hit was the argonaute 1 (ago1) gene, a central element of the microRNA (miRNA) translational silencing machinery. Further studies confirmed the physiological role of the miRNA machinery in HIF–dependent transcription. This study reveals the occurrence of novel mechanisms of HIF regulation, which might contribute to developing novel strategies for therapeutic intervention of HIF–related pathologies, including heart attack, cancer, and stroke.
Highlights
The cellular response to low oxygen tension involves changes in gene expression that mediate adaptation to this condition
Adaptation of cells to low oxygen is a physiological response related to important diseases, including heart attacks, stroke, cancer, and diabetes
The master regulator of cellular responses to hypoxia is a transcription factor named Hypoxia Inducible Factors (HIFs), which induces a set of genes that mediate adaptation to oxygen starvation
Summary
The cellular response to low oxygen tension (hypoxia) involves changes in gene expression that mediate adaptation to this condition. HIFs are a/b heterodimers, in which the common b subunit is constitutive and a subunits are negatively regulated by O2 through several concurrent mechanisms that include oxygen-dependent proteasomal degradation [2], blockage of transcriptional co-activator recruitment [3,4] and subcellular localization [5,6]. Sima is stable in hypoxia but rapidly degraded in normoxic conditions; its degradation requires Fatiga-dependent hydroxylation of a specific prolyl residue localized in the Sima ODDD [12,14]. Various small molecule screens searching for HIF regulators have been conducted using high-throughput approaches (see [18] for a review). These strategies have been instrumental for manipulating HIF-dependent transcription, they have resulted less informative for the identification of the molecular targets involved. Among the genes identified as novel regulators of HIF-dependent transcription, we found the chromatin modifying elements Reptin and Pontin, several transcriptional and translational regulators, and the miRNA pathway component Argonaute
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