Dissecting the genetic and molecular networks underlying longevity and aging

Princeton University, Princeton NJ

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Abstract

? DESCRIPTION (provided by applicant): Reduced insulin/IGF-1-like signaling (IIS) extends C. elegans lifespan by up-regulating stress response (Class I) and down-regulating development (Class II) genes through a mechanism that depends on the conserved transcription factor DAF-16/FOXO. By integrating a genomewide analysis of gene expression responsiveness to DAF-16 with genomewide in vivo binding data for a compendium of transcription factors, we discovered that the transcriptional activator PQM-1 directly controls Class II genes by binding to the DAF-16 associated element (DAE). DAF-16 directly regulates Class I genes only, through the DAF-16 binding element (DBE). Loss of PQM-1 suppresses daf-2 and eat-2 longevity as well as thermotolerance, and further slows development. The nuclear presence of PQM-1 and DAF- 16 is controlled by IIS in opposite ways, and, surprisingly, was found to be mutually exclusive. We also observe progressive loss of nuclear PQM-1 with age, explaining declining expression of PQM-1 targets. Together, our data suggest an elegant mechanism for switching between stress response and development. The overall goal of this project is to elucidate the mechanisms underlying the observed antagonistic relationship between PQM-1 and DAF-16. We will employ high-throughput screens based on reporter assays and microfluidics microscopy to identify genetic and small-molecule regulators of PQM-1 translocation. Additionally, we will use mass spectrometry to identify PQM-1's post-translational modifications and protein interactors, and determine how these affect nuclear translocation. We will also identify factors responsible for the nuclear exit of DAF-16 and PQM-1 with age. Finally, we will identify PQM-1 homologs in mammalian cells that exhibit a similar antagonism with FOXOs. Together, our results and insights will provide a framework for understanding how PQM-1 and DAF-16 and its mammalian counterparts allow cells to strike a balance between development and stress response.