NHR-49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

Endogenous and exogenous stresses elicit transcriptional responses that limit damage and promote cell/organismal survival. Like its mammalian counterparts, Hepatocyte Nuclear Factor 4 (HNF4) and peroxisome proliferator-activated receptor a (PPARa), Caenorhabditis elegans NHR-49 is a well-established regulator of lipid metabolism. Here, we reveal that NHR-49 is essential to activate a transcriptional response common to organic peroxide and fasting, which includes the pro-longevity gene fmo-2/flavin-containing monoxygenase. These NHR-49-dependent, stress-responsive genes are also upregulated in long-lived glp-1/notch receptor mutants, and two of them contribute to increased oxidative stress resistance in wild-type worms and long-lived glp-1 mutants. Similar to its role in lipid metabolism, NHR-49 requires the Mediator subunit mdt-15 to promote stress-induced gene expression. However, NHR-49 acts independently from the transcription factor hlh-30/TFEB that also promotes fmo-2 expression. Similarly, activation of the p38 MAPK, PMK-1, which is important for adaptation to a variety of stresses, is only important for peroxide-induced expression of a subset of NHR-49-dependent genes, including fmo-2. Notably, we find that organic peroxide increases NHR-49 protein levels, apparently by a post-transcriptional mechanism that does not require PMK-1 activation. Together these findings establish a new role for the HNF4/PPARa-related NHR-49 as a stress-activated regulator of cytoprotective gene expression.

Dataset features

Information

Specifications

Application:	RNA-seq analysis
Number of samples:	8
Release date:	Mar 5 2018
Last update date:	Mar 5 2018
Access:	Public
Genes:	nhr-49, HNF4A, PPARA, FMO2, GLP1R, TFEB
Taxon:	Caenorhabditis elegans, Homo sapiens
Dataset link	NHR-49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

Experimental Protocol

Transcriptomes analysis of L4 stage wild-type (N2) and nhr-49(nr2041) worms (+/- tBOOH) using RNA sequencing in duplicate.

Repositories

GEO

GSE107799

ENA

SRP126312

BioProject

PRJNA421426

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Contact

Forum Bhanshali