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.
Highlights
The role of RNA interference (RNAi) in the silencing of transposons and other repetitive elements is well documented [1,2], while the knowledge of its impact on endogenous genes and signaling pathways is limited
We find that transcription of one of the insulinsignaling genes is inhibited by mechanisms involving chromatin and RNA interference, a silencing process that depends on short RNAs
We demonstrate that mutants deficient in RNA interference are more susceptible to stress due to increased insulin signaling and that increased dosage of a chromatin-binding protein repressing insulin signaling and promoting RNA interference leads to better survival of nematodes grown under oxidative stress conditions
Summary
The role of RNA interference (RNAi) in the silencing of transposons and other repetitive elements is well documented [1,2], while the knowledge of its impact on endogenous genes and signaling pathways is limited. In this article we investigate the remarkable and similar effects of the Caenorhabditis elegans RNAipromoting factors RNAi DEficient 4 (RDE-4) [3] and Zinc Finger Protein 1 (ZFP-1) on the expression of stress-related genes. ZFP-1, a Plant Homeo Domain (PHD) zinc finger protein, was first identified as a factor promoting RNAi interference in C. elegans [5,6,7]. It is a homolog of mammalian AF10 (Acute Lymphoblastic Leukemia 1-Fused gene from chromosome 10) [8] and plays a key role in leukemias caused by Mixed Lineage Leukemia MLL-AF10 fusion due to the recruitment of histone methyltransferase Dot by the AF10 portion of the fusion protein [9]. The effects of rde-4 loss-of-function are likely to be related to recently identified endogenous siRNAs
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