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

  1. Kelsie RS Doering
  2. Xuanjin Cheng
  3. Luke Milburn
  4. Ramesh Ratnappan
  5. Arjumand Ghazi
  6. Dana L Miller
  7. Stefan Taubert  Is a corresponding author
  1. University of British Columbia, Canada
  2. University of Washington, United States
  3. University of Pittsburgh School of Medicine, United States

Abstract

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.

Data availability

RNA-seq data have been deposited at NCBI Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) under the record GSE166788.All data generated or analysed during this study are included in the manuscript and Supplementary Tables. Raw data points from each N are shown in figures where-ever possible. See transparent reporting form for details.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Kelsie RS Doering

    Graduate Program in Medical Genetics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Xuanjin Cheng

    Department of Medical Genetics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Luke Milburn

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ramesh Ratnappan

    Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7055-9043
  5. Arjumand Ghazi

    Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Dana L Miller

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3983-0493
  7. Stefan Taubert

    Graduate Program in Medical Genetics, University of British Columbia, Vancouver, Canada
    For correspondence
    taubert@cmmt.ubc.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2432-7257

Funding

National Institutes of Health (R56AG066682)

  • Arjumand Ghazi

BC Children's Hospital Foundation

  • Stefan Taubert

Natural Sciences and Engineering Research Council of Canada (RGPIN-2018-05133)

  • Stefan Taubert

National Institutes of Health (R01AG051659)

  • Arjumand Ghazi

Cancer Research Society (22727)

  • Stefan Taubert

BC Children's Hospital Foundation

  • Kelsie RS Doering

Canada Research Chairs

  • Stefan Taubert

National Institutes of Health (R01AG044378)

  • Dana L Miller

Natural Sciences and Engineering Research Council of Canada

  • Kelsie RS Doering

Canadian Institutes of Health Research (PJT-153199)

  • Stefan Taubert

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Douglas Portman, University of Rochester, United States

Publication history

  1. Preprint posted: February 24, 2021 (view preprint)
  2. Received: February 26, 2021
  3. Accepted: March 12, 2022
  4. Accepted Manuscript published: March 14, 2022 (version 1)
  5. Version of Record published: March 28, 2022 (version 2)

Copyright

© 2022, Doering et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Kelsie RS Doering
  2. Xuanjin Cheng
  3. Luke Milburn
  4. Ramesh Ratnappan
  5. Arjumand Ghazi
  6. Dana L Miller
  7. Stefan Taubert
(2022)
Nuclear Hormone Receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in Caenorhabditis elegans
eLife 11:e67911.
https://doi.org/10.7554/eLife.67911
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