A Conserved PHD Finger Protein and Endogenous RNAi Modulate Insulin Signaling in <i>Caenorhabditis elegans</i>

Abstract

<div><p>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 <i>Caenorhabditis elegans</i>, 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 <i>pdk-1</i> in <i>zfp-1</i> and <i>rde-4</i> 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 <i>pdk-1</i> transcription was important for the extended lifespan of the <i>age-1(hx546)</i> reduction-of-function PI3 kinase mutant, since the lifespan of the <i>age-1; zfp-1</i> double mutant strain was significantly shorter compared to <i>age-1(hx546)</i>. 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.</p></div>