Role of Histone Methyltransferase SET-4 in Developmental Plasticity and Longevity

[摘要] FoxO transcription factors promote longevity across diverse organisms through upregulation ofparallel stress responses. Therefore, understanding how FoxO activity is regulated may provideinsights for improving overall vitality in an aging population. Insulin and insulin-like growthfactor signaling (IIS) is highly conserved across metazoans and antagonizes FoxO function.Decreasing IIS pathway activity increases lifespan in model organisms and may be conserve inhumans. This association between FoxO transcription factors and longevity was first discoveredin studies using the free living nematode Caenorhabditis elegans. In C. elegans, the DAF-2/IISpathway also influences dauer diapause. Dauer is a state of larval developmental diapause thatoccurs in response to stressful environmental conditions including population stress perceivedthrough elaboration of a complex pheromone mixture. Mutations that reduce DAF-2/IIS pathwayactivity arrest as dauers in a manner requiring the FoxO transcription factor DAF-16. When AKTactivity is reduced, DAF-16/FoxO translocates to the nucleus, where it is inhibited by EAK-7/TLDC1, a conserved protein of unknown function. eak-7;akt-1 double mutants always arrest asdauers. We designed a forward genetic screen to discover novel regulators of DAF-16/FOXO bymutagenizing eak-7;akt-1 worms and looking for suppressors of eak-7;akt-1 dauer arrest (seakmutants). Whole genome sequencing revealed one seak mutant strain harbored a mutation in set-4, which encodes a conserved histone H4 lysine 20 (H4K20) methyltransferase. SET-4 isrequired for dauer arrest in both reduced IIS mutant backgrounds and in response to dauerinducing pheromone. SET-4 promotes dauer arrest only in XX hermaphrodites, not XO males,consistent with existing data that SET-4 participates in dosage compensation of X chromosomes.We found that neuron-specific overexpression of set-4 rescued dauer arrest in set-4 mutants to asimilar extent as the native promoter. SET-4 acts together with DAF-16/FoxO in specific sensoryneurons to silence expression of the X-linked insulin-like peptide ins-9. Loss of ins-9 rescues thexviidauer-defective phenotype observed in set-4 mutants in response to pheromone. ins-9 itself isalso sensitive to dauer pheromone. Taken together, these data implicate chromatin remodeling asa novel mechanism that regulates FoxO transcription factor activity. Since epigenetic marks likehistone methylation are sensitive to environmental interventions, these findings may lead to newtherapies for chronic diseases associated with aging.

[发布机构] University of Michigan

[效力级别] aging

[关键词] epigenetics;aging;insulin;Genetics;Geriatrics;Molecular;Cellular and Developmental Biology;Health Sciences;Science;Cell and Developmental Biology