A conserved PHD finger protein and endogenous RNAi modulate insulin signaling in Caenorhabditis elegans

• Published in: PLoS genetics 2011-09, Vol.7 (9), p.e1002299-e1002299
• Main Authors: Mansisidor, Andres R, Cecere, Germano, Hoersch, Sebastian, Jensen, Morten B, Kawli, Trupti, Kennedy, Lisa M, Chavez, Violeta, Tan, Man-Wah, Lieb, Jason D, Grishok, Alla
• Format: Article
• Language: English
• Subjects: Animals; Biology; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cellular signal transduction; Epigenesis, Genetic; Forkhead Transcription Factors; Gene Expression Regulation; Genes; Genetic aspects; Insulin - genetics; Insulin - metabolism; Kinases; Longevity - genetics; Nematodes; Oxidative Stress - genetics; Paraquat - pharmacology; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Physiological aspects; Proteins; RNA Interference; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Signal Transduction - genetics; Transcription Factors - genetics; Transcription Factors - metabolism; Zinc finger proteins
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1002299

Insulin signaling has a profound effect on longevity and the oxidative stress resistance of animals. Inhibition of insulin signaling results in the activation of DAF-16/FOXO and SKN-1/Nrf transcription factors and increased animal fitness. By studying the biological functions of the endogenous RNA interference factor RDE-4 and conserved PHD zinc finger protein ZFP-1 (AF10), which regulate overlapping sets of genes in Caenorhabditis elegans, we identified an important role for these factors in the negative modulation of transcription of the insulin/PI3 signaling-dependent kinase PDK-1. Consistently, increased expression of pdk-1 in zfp-1 and rde-4 mutants contributed to their reduced lifespan and sensitivity to oxidative stress and pathogens due to the reduction in the expression of DAF-16 and SKN-1 targets. We found that the function of ZFP-1 in modulating pdk-1 transcription was important for the extended lifespan of the age-1(hx546) reduction-of-function PI3 kinase mutant, since the lifespan of the age-1; zfp-1 double mutant strain was significantly shorter compared to age-1(hx546). We further demonstrate that overexpression of ZFP-1 caused an increased resistance to oxidative stress in a DAF-16-dependent manner. Our findings suggest that epigenetic regulation of key upstream signaling components in signal transduction pathways through chromatin and RNAi may have a large impact on the outcome of signaling and expression of numerous downstream genes.