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

ELife
Corinne L Pender, H Robert Horvitz

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.

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Citations

Feb 24, 2019·Biogerontology·Jingnu XiaPetros Ligoxygakis
Feb 23, 2021·Journal of Toxicology and Environmental Health. Part B, Critical Reviews·Jessica H HartmanJoel N Meyer

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Datasets Mentioned

BETA
GSE108283

Methods Mentioned

BETA
RNA-seq
ChIP-chip
ChIP-seq
transgenic
PCR
dissecting

Software Mentioned

Bioconductor
RSEM
bwa
edgeR
bedtools
samtools
bowtie
GOrilla
glmQLFTest
ZEN

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