title: A conserved PHD finger protein and endogenous RNAi modulate insulin signaling in Caenorhabditis elegans.
abstract: 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.
authors: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, United States of America.
authors: Andres R
authors: AR
authors: Mansisidor
authors: Germano
authors: G
authors: Cecere
authors: Sebastian
authors: S
authors: Hoersch
authors: Morten B
authors: MB
authors: Jensen
authors: Trupti
authors: T
authors: Kawli
authors: Lisa M
authors: LM
authors: Kennedy
authors: Violeta
authors: V
authors: Chavez
authors: Man-Wah
authors: MW
authors: Tan
authors: Jason D
authors: JD
authors: Lieb
authors: Alla
authors: A
authors: Grishok
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D008136:Longevity / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D010269:Paraquat / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D007328:Insulin; C461645:RDE-4 protein, C elegans; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C554867:Y95B8A.8 protein, C elegans; C579560:Zfp-1 protein, C elegans; C108831:daf-16 protein, C elegans; D019869:Phosphatidylinositol 3-Kinases; D010269:Paraquat