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PLoS Genet. 2011 Sep;7(9):e1002299. doi: 10.1371/journal.pgen.1002299. Epub 2011 Sep 29.

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

Author information

1
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, United States of America.

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.

PMID:
21980302
PMCID:
PMC3183084
DOI:
10.1371/journal.pgen.1002299
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors have declared that no competing interests exist.

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