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Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in Caenorhabditis elegans

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 with HIF to mediate the physiological hypoxia response. Here, we describe a hypoxia response pathway controlled...

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Autores principales: Doering, Kelsie RS, Cheng, Xuanjin, Milburn, Luke, Ratnappan, Ramesh, Ghazi, Arjumand, Miller, Dana L, Taubert, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8959602/
https://www.ncbi.nlm.nih.gov/pubmed/35285794
http://dx.doi.org/10.7554/eLife.67911
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author Doering, Kelsie RS
Cheng, Xuanjin
Milburn, Luke
Ratnappan, Ramesh
Ghazi, Arjumand
Miller, Dana L
Taubert, Stefan
author_facet Doering, Kelsie RS
Cheng, Xuanjin
Milburn, Luke
Ratnappan, Ramesh
Ghazi, Arjumand
Miller, Dana L
Taubert, Stefan
author_sort Doering, Kelsie RS
collection PubMed
description 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 with HIF to mediate the physiological hypoxia response. Here, we describe a 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 animal survival in hypoxia and is synthetic lethal with hif-1 in this context, demonstrating that these factors act in parallel. 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 with the well-known HIF-mediated hypoxia response.
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spelling pubmed-89596022022-03-29 Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in Caenorhabditis elegans Doering, Kelsie RS Cheng, Xuanjin Milburn, Luke Ratnappan, Ramesh Ghazi, Arjumand Miller, Dana L Taubert, Stefan eLife Chromosomes and Gene Expression 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 with HIF to mediate the physiological hypoxia response. Here, we describe a 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 animal survival in hypoxia and is synthetic lethal with hif-1 in this context, demonstrating that these factors act in parallel. 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 with the well-known HIF-mediated hypoxia response. eLife Sciences Publications, Ltd 2022-03-14 /pmc/articles/PMC8959602/ /pubmed/35285794 http://dx.doi.org/10.7554/eLife.67911 Text en © 2022, Doering et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Chromosomes and Gene Expression
Doering, Kelsie RS
Cheng, Xuanjin
Milburn, Luke
Ratnappan, Ramesh
Ghazi, Arjumand
Miller, Dana L
Taubert, Stefan
Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in Caenorhabditis elegans
title Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in Caenorhabditis elegans
title_full Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in Caenorhabditis elegans
title_fullStr Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in Caenorhabditis elegans
title_full_unstemmed Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in Caenorhabditis elegans
title_short Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in Caenorhabditis elegans
title_sort nuclear hormone receptor nhr-49 acts in parallel with hif-1 to promote hypoxia adaptation in caenorhabditis elegans
topic Chromosomes and Gene Expression
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8959602/
https://www.ncbi.nlm.nih.gov/pubmed/35285794
http://dx.doi.org/10.7554/eLife.67911
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