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

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Abstract

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.

Data availability

Sequencing data have been deposited in GEO under accession code GSE108283.

The following data sets were generated

1. Pender CL
2. Horvitz HR
(2017) The HIF hypoxia-response pathway drives hormonal signaling to promote stress resistance and modulate behavior of C. elegans
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE108283).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE108283

Article and author information

Author details

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.
H Robert Horvitz

Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, United States

For correspondence
horvitz@mit.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9964-9613

Funding

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.

Copyright

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.