{"doi":"10.1101/2021.02.24.432575","title":"Nuclear Hormone Receptor NHR-49 controls a HIF-1-independent hypoxia adaptation pathway in <i>Caenorhabditis elegans</i>","abstract":"Abstract The response to insufficient oxygen (hypoxia) is orchestrated by the conserved Hypoxia-Inducible Factor (HIF). However, HIF-independent hypoxia response pathways exist that act in parallel to HIF to mediate the physiological hypoxia response. Here, we describe a HIF-independent hypoxia response pathway controlled by Caenorhabditis elegans Nuclear Hormone Receptor NHR-49, an orthologue of mammalian Peroxisome Proliferator-Activated Receptor alpha (PPARα). We show that nhr-49 is required for worm survival in hypoxia and is synthetic lethal with hif-1 in this context, demonstrating that these factors act independently. RNA-seq analysis shows that in hypoxia nhr-49 regulates a set of genes that are hif-1- independent, including autophagy genes that promote hypoxia survival. We further show that Nuclear Hormone Receptor nhr-67 is a negative regulator and Homeodomain-interacting Protein Kinase hpk-1 is a positive regulator of the NHR-49 pathway. Together, our experiments define a new, essential hypoxia response pathway that acts in parallel to the well-known HIF-mediated hypoxia response.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":223269,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":824747,"name":"Xuanjin Cheng","orcid":"0000-0002-2119-1788","position":1,"is_corresponding":false},{"id":825246,"name":"Luke Milburn","orcid":null,"position":2,"is_corresponding":false},{"id":380505,"name":"Ramesh Ratnappan","orcid":"0000-0001-7055-9043","position":3,"is_corresponding":false},{"id":392144,"name":"Arjumand Ghazi","orcid":"0000-0002-5859-4206","position":4,"is_corresponding":false},{"id":824748,"name":"Dana L. Miller","orcid":"0000-0003-3983-0493","position":5,"is_corresponding":false},{"id":295630,"name":"Stefan Taubert","orcid":"0000-0002-2432-7257","position":6,"is_corresponding":false},{"id":824746,"name":"Kelsie R. S. Doering","orcid":"0000-0003-3485-7419","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-18T23:54:11.061295Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}