Project description:Transcriptional profiling of C. elegans NHR-49, NHR-66 and NHR-80 Independent data sets were generated for each mutant vs wildtpe comparison: NHR-49 (N=2), NHR-66 (N=3), NHR-80 (N=4)
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:Sphingolipids are required for diverse biological functions and are degraded by specific catabolic enzymes. However, the mechanisms that regulate sphingolipid catabolism are not known. Here we characterize a transcriptional axis that regulates sphingolipid breakdown to control resistance against bacterial infection. From an RNAi screen for transcriptional regulators of pathogen resistance in the nematode C. elegans, we identified the nuclear hormone receptor nhr-66, a ligand-gated transcription factor homologous to human hepatocyte nuclear factor 4. Tandem chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA sequencing (RNA-seq) experiments revealed that NHR-66 is a transcriptional repressor, which directly targets sphingolipid catabolism genes. Transcriptional de-repression of two sphingolipid catabolic enzymes in nhr-66 loss-of-function mutants drives the breakdown of sphingolipids, which enhances host susceptibility to infection with the bacterial pathogen Pseudomonas aeruginosa. These data define transcriptional control of sphingolipid catabolism in the regulation of cellular sphingolipids, a process that is necessary for pathogen resistance.
Project description:To identify genes transcriptionally regulated by the nuclear hormone receptor, NHR-49, we performed RNA sequencing of wild-type and nhr-49(nr2041) loss-of-function mutant C. elegans. This transcriptomic dataset is utilized in the respective study to compare differentially regulated genes in nhr-49(nr2041) mutant worms to those treated with hsf-1 RNAi.
