Condition‐adapted stress and longevity gene regulation by Caenorhabditis elegans SKN‐1/Nrf

Abstract

SummaryStudies in model organisms have identified regulatory processes that profoundly influence aging, many of which modulate resistance against environmental or metabolic stresses. In Caenorhabditis elegans, the transcription regulator SKN-1 is important for oxidative stress resistance and acts in multiple longevity pathways. SKN-1 is the ortholog of mammalian Nrf proteins, which induce Phase 2 detoxification genes in response to stress. Phase 2 enzymes defend against oxygen radicals and conjugate electrophiles that are produced by Phase 1 detoxification enzymes, which metabolize lipophilic compounds. Here, we have used expression profiling to identify genes and processes that are regulated by SKN-1 under normal and stress-response conditions. Under nonstressed conditions SKN-1 upregulates numerous genes involved in detoxification, cellular repair, and other functions, and downregulates a set of genes that reduce stress resistance and lifespan. Many of these genes appear to be direct SKN-1 targets, based upon presence of predicted SKN-binding sites in their promoters. The metalloid sodium arsenite induces skn-1-dependent activation of certain detoxification gene groups, including some that were not SKN-1-upregulated under normal conditions. An organic peroxide also triggers induction of a discrete Phase 2 gene set, but additionally stimulates a broad SKN-1-independent response. We conclude that under normal conditions SKN-1 has a wide range of functions in detoxification and other processes, including modulating mechanisms that reduce lifespan. In response to stress, SKN-1 and other regulators tailor transcription programs to meet the challenge at hand. Our findings reveal striking complexity in SKN-1 functions and the regulation of systemic detoxification defenses.

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

“…qPCR analysis of nhr‐49 ( et13 ) worms also revealed higher levels of fmo‐2 and K05B2.4 mRNA, although other tested tBOOH‐ and fasting‐induced genes were only modestly induced (Figure 3b, data not shown). In contrast, the expression of arsenite‐responsive genes ( gst‐4 , gcs‐1 , gst‐6 , ptps‐1 ), which require skn‐1 and mdt‐15 for activation (Goh et al., 2014; Oliveira et al., 2009), was not increased in nhr‐49 gof mutants (Figure S2b). Thus, our data suggest that NHR‐49‐dependent oxidative stress gene activation is distinct from the SKN‐1‐dependent response to arsenite.…”

“…The fmo‐2p::gfp reporter was also activated by DTT and H 2 O 2 , but not by arsenite and cadmium (Figure S1b). Thus, consistent with other studies, our transcriptional reporter was strongly activated by tBOOH but not by stimuli that activate SKN‐1‐dependent gene expression (Goh et al., 2014; Oliveira et al., 2009). …”

“…(a) Venn diagrams show the overlaps between genes upregulated by tBOOH in a SKN‐1‐independent manner (Oliveira et al., 2009), upregulated after 9 hr of fasting (Uno et al., 2013), and upregulated in the glp‐1 ( bn18 ) mutant (Steinbaugh et al., 2015). p  <   2.2 × 10 −16 , p  =   .0001892, and p  =   1.598 × 10 −09 , respectively (Fisher's exact test).…”

“…Thus, mdt‐15 may promote both NHR‐49 and SKN‐1‐dependent gene expression in germline‐deficient glp‐1 mutant animals, including different subsets of lipid metabolic and cytoprotective genes. Notably, although both transcription factors require MDT‐15, nhr‐49 does not activate arsenite‐responsive genes (Figure S2b) and skn‐1 is dispensable for most tBOOH‐induced gene expression (Oliveira et al., 2009). Thus, NHR‐49 and SKN‐1 are both important in stress conditions and in long‐lived glp‐1 mutants, but partner with MDT‐15 to coordinate expression of distinct gene sets that may be more important under particular conditions.…”

“…Nevertheless, distinct responses are initiated in response to different oxidants (Blackwell et al., 2015; Wu, Deonarine, Przybysz, Strange & Choe, 2016). For example, the organic peroxide tert‐butyl‐hydroperoxide (tBOOH) elicits a transcriptional response that is largely skn‐1 ‐independent (Oliveira et al., 2009). Notably, mdt‐15 , a subunit of the mediator transcriptional coregulator that is required for skn‐1 ‐dependent stress responses, is also required for the skn‐1‐ independent transcriptional response to tBOOH (Goh et al., 2014; Taubert, Hansen, Van Gilst, Cooper & Yamamoto, 2008).…”