Project description:The response to insufficient oxygen, termed hypoxia, is orchestrated by the conserved master regulator Hypoxia-Inducible Factor-1 (HIF-1), which is hyperactive in many cancers. Here, we describe a HIF-1 independent hypoxia response pathway controlled by Caenorhabditis elegans Nuclear Hormone Receptor NHR-49, an orthologue of mammalian lipid metabolism regulator Peroxisome Proliferator-Activated Receptor alpha (PPARα). nhr-49 is required for worm survival in hypoxia and is synthetically lethal with hif-1 in this context, demonstrating independent activity. RNA-seq data show that nhr-49 regulates a set of hif-1 independent hypoxia responsive genes, including autophagy genes that promote hypoxia survival. We further identified the Nuclear Hormone Receptor nhr-67 as a negative regulator and the Homeodomain-interacting Protein Kinase hpk-1 as a positive regulator in the NHR-49 pathway. Together, our experiments describe an essential hypoxia response pathway controlled by nhr-49 that includes new upstream and downstream components and is as important as hif-1 dependent hypoxia adaptation.
Project description:Hypoxia-inducible transcription factor HIF is the key regulator of hypoxia response. It is conserved from human to the model organism C. elegans. The homolog of HIF in C. elegans is HIF-1. In C. elegans, there are six alternative splicing isoforms for HIF-1. Isoform a (HIF1a) is the predominant one with important biological functions for stress response and longevity. Here, by performing chromatin immunoprecipitation DNA-sequencing (ChIP-seq), we identified the direct targets for HIF-1a at whole genome level.
