Nuclear Hormone Receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in Caenorhabditis elegans
- University of British Columbia, Canada
- University of Washington, United States
- 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.
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NHR-49 controls a HIF-1 independent hypoxia adaptation pathway in Caenorhabditis elegansNCBI Gene Expression Omnibus GSE166788.
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Hypoxia responseGene expression omnibus GSE2836.
Article and author information
Author details
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
- Douglas Portman, University of Rochester, United States
Publication history
- Preprint posted: February 24, 2021 (view preprint)
- Received: February 26, 2021
- Accepted: March 12, 2022
- Accepted Manuscript published: March 14, 2022 (version 1)
- 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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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
Further reading
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N6-methyladenosine (m6A) RNA modification impacts mRNA fate primarily via reader proteins, which dictate processes in development, stress, and disease. Yet little is known about m6A function in Saccharomyces cerevisiae, which occurs solely during early meiosis. Here we perform a multifaceted analysis of the m6A reader protein Pho92/Mrb1. Cross-linking immunoprecipitation analysis reveals that Pho92 associates with the 3’end of meiotic mRNAs in both an m6A-dependent and independent manner. Within cells, Pho92 transitions from the nucleus to the cytoplasm, and associates with translating ribosomes. In the nucleus Pho92 associates with target loci through its interaction with transcriptional elongator Paf1C. Functionally, we show that Pho92 promotes and links protein synthesis to mRNA decay. As such, the Pho92-mediated m6A-mRNA decay is contingent on active translation and the CCR4-NOT complex. We propose that the m6A reader Pho92 is loaded co-transcriptionally to facilitate protein synthesis and subsequent decay of m6A modified transcripts, and thereby promotes meiosis.
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Transcription factors (TFs) are classically attributed a modular construction, containing well-structured sequence-specific DNA-binding domains (DBDs) paired with disordered activation domains (ADs) responsible for protein-protein interactions targeting co-factors or the core transcription initiation machinery. However, this simple division of labor model struggles to explain why TFs with identical DNA-binding sequence specificity determined in vitro exhibit distinct binding profiles in vivo. The family of hypoxia-inducible factors (HIFs) offer a stark example: aberrantly expressed in several cancer types, HIF-1α and HIF-2α subunit isoforms recognize the same DNA motif in vitro – the hypoxia response element (HRE) – but only share a subset of their target genes in vivo, while eliciting contrasting effects on cancer development and progression under certain circumstances. To probe the mechanisms mediating isoform-specific gene regulation, we used live-cell single particle tracking (SPT) to investigate HIF nuclear dynamics and how they change upon genetic perturbation or drug treatment. We found that HIF-α subunits and their dimerization partner HIF-1β exhibit distinct diffusion and binding characteristics that are exquisitely sensitive to concentration and subunit stoichiometry. Using domain-swap variants, mutations, and a HIF-2α specific inhibitor, we found that although the DBD and dimerization domains are important, another main determinant of chromatin binding and diffusion behavior is the AD-containing intrinsically disordered region (IDR). Using Cut&Run and RNA-seq as orthogonal genomic approaches, we also confirmed IDR-dependent binding and activation of a specific subset of HIF target genes. These findings reveal a previously unappreciated role of IDRs in regulating the TF search and binding process that contribute to functional target site selectivity on chromatin.
