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Hypoxia-inducible factor cell non-autonomously regulates C. elegans stress responses and behavior via a nuclear receptor

  1. Corinne L Pender
  2. H Robert Horvitz  Is a corresponding author
  1. Howard Hughes Medical Institute, Massachusetts Institute of Technology, United States
Research Article
  • Cited 2
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Cite this article as: eLife 2018;7:e36828 doi: 10.7554/eLife.36828


The HIF (hypoxia-inducible factor) transcription factor is the master regulator of the metazoan response to chronic hypoxia. In addition to promoting adaptations to low oxygen, HIF drives cytoprotective mechanisms in response to stresses and modulates neural circuit function. How most HIF targets act in the control of the diverse aspects of HIF-regulated biology remains unknown. We discovered that a HIF target, the C. elegans gene cyp-36A1, is required for numerous HIF-dependent processes, including modulation of gene expression, stress resistance, and behavior. cyp-36A1 encodes a cytochrome P450 enzyme that we show controls expression of more than a third of HIF-induced genes. CYP-36A1 acts cell non-autonomously by regulating the activity of the nuclear hormone receptor NHR-46, suggesting that CYP-36A1 functions as a biosynthetic enzyme for a hormone ligand of this receptor. We propose that regulation of HIF effectors through activation of cytochrome P450 enzyme/nuclear receptor signaling pathways could similarly occur in humans.

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Author details

  1. Corinne L Pender

    Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. H Robert Horvitz

    Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9964-9613


National Institutes of Health (GM024663)

  • Corinne L Pender
  • H Robert Horvitz

Howard Hughes Medical Institute

  • Corinne L Pender
  • H Robert Horvitz

National Institutes of Health (T32GM007287)

  • Corinne L Pender

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

Reviewing Editor

  1. Matt Kaeberlein, University of Washington, United States

Publication history

  1. Received: March 21, 2018
  2. Accepted: July 15, 2018
  3. Accepted Manuscript published: July 16, 2018 (version 1)
  4. Version of Record published: August 6, 2018 (version 2)


© 2018, Pender & Horvitz

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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