Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/Nrf.
Studies 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.
Oliveira
Riva P
RP
Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Department of Pathology, Harvard Medical School, Harvard Stem Cell Institute, One Joslin Place, Boston, MA 02215, USA.
Porter Abate
Jess
J
Dilks
Kieran
K
Landis
Jessica
J
Ashraf
Jasmine
J
Murphy
Coleen T
CT
Blackwell
T Keith
TK
D000818:Animals; D018053:Arsenites / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D018509:DNA, Helminth / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D008136:Longevity / Q000235:genetics*; D051265:NF-E2-Related Factor 1 / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D018053:Arsenites; D029742:Caenorhabditis elegans Proteins; D018509:DNA, Helminth; D004268:DNA-Binding Proteins; D051265:NF-E2-Related Factor 1; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C073702:skn-1 protein, C elegans; D020122:tert-Butylhydroperoxide; C015001:arsenite