Abstract
FOXO transcription factors have long been associated with longevity control and tissue homeostasis. Although the transcriptional regulation of FOXO have been previously characterized (especially in long-lived insulin mutants and under stress conditions), how normal aging impacts the transcriptional activity of FOXO is poorly understood. Here, we conducted a chromatin immunoprecipitation sequencing (ChIP-Seq) analysis in both young (2-week-old) and aged (5-week-old) wild-type female fruit flies, Drosophila melanogaster, to evaluate the dynamics of FOXO gene targeting during aging. Intriguingly, the number of FOXO-bound genes dramatically decreases with age (from 2617 to 224). Consistent to the reduction of FOXO binding activity, many genes targeted by FOXO in young flies are transcriptionally altered with age, either up-regulated (FOXO-repressing genes) or down-regulated (FOXO-activating genes) in adult head tissue. In addition, we show that many FOXO-bound genes in wild-type flies are unique from those in insulin receptor substrate chico mutants. Distinct from chico mutants, FOXO targets specific cellular processes (e.g., actin cytoskeleton) and signaling pathways (e.g., Hippo, MAPK) in young wild-type female flies. FOXO targeting on these pathways decreases with age. Interestingly, FOXO targets in aged flies are enriched in cellular processes like chromatin organization and nucleosome assembly. Furthermore, FOXO binding to core histone genes is well maintained at aged flies. Together, our findings provide new insights into dynamic FOXO targeting under normal aging and highlight the diverse and understudied regulatory mechanisms for FOXO transcriptional activity.
Highlights
The process of aging is accompanied by a decline in physiological function and cellular maintenance
FOXO proteins were first implemented in lifespan extension in Caenorhabditis elegans where insulin-like receptor mutant daf-2 extends lifespan via FOXO homolog daf-16 (Kenyon et al, 1993)
These results suggest that FOXO could be activated in wellfed wild-type flies to regulate the expression of its target genes, which is consistent with recent Chromatin immunoprecipitation (ChIP)-Seq studies (Alic et al, 2011; Riedel et al, 2013)
Summary
The process of aging is accompanied by a decline in physiological function and cellular maintenance. FOXO functions downstream of insulin/insulin-like growth factor (insulin/IGF) signaling and is negatively regulated by PI3K-Akt. FOXO Binding Declines With Age pathway (Brunet et al, 1999). It is generally believed that insulin/IGF signaling declines with age This is primarily based on age-dependent decrease in the expression of FOXO target genes (Demontis and Perrimon, 2010; Rera et al, 2012). It remains to be determined how aging impacts FOXO transcriptional activity and DNA binding capacity of FOXO transcription factors. Our findings provide new evidence linking age-dependent FOXO transcriptional activity to its role in longevity control and tissue maintenance
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