Figure 2.
FOXO binding is conserved between Caenorhabditis elegans and mouse, and conserved targets are transcriptionally regulated and function in cellular maintenance and repair. (A) Overlap between FOXO target genes in all mouse tissues and FOXO/DAF‐16 target genes (union of wild‐type and daf‐2 mutants) in C. elegans (P = 5.18 × 10−15, Fisher's exact test; all unique mouse–C. elegans orthologs were used as background; 8072 genes). (B) An example of conserved FOXO/DAF‐16 at a specific target, Arrdc3/arrd‐10, in mouse and C. elegans. (C) PANTHER Biological Process and (D) PANTHER Pathway analysis of conserved FOXO/DAF‐16 target genes. (E) Enrichment for conserved FOXO/DAF‐16 binding sites (overlap in (A)) among genes downregulated in Foxo1 knockout Treg cells compared to wild‐type. Genes are ranked (X‐axis) by fold change and binned into 35 bins, with genes most downregulated in Foxo1 −/− on the left. The number of conserved FOXO targets was calculated for each bin and plotted on the Y‐axis. Filled circles depict statistically significant enrichment in direct binding (P < 0.05, Monte Carlo simulation with Benjamini–Hochberg correction). (F) Same analysis as described in (E), but enrichment is shown for targets upregulated by FOXO/DAF‐16 (left) or downregulated by FOXO/DAF‐16 (right). (G) PANTHER Biological Process analysis of mouse/worm conserved targets that are also activated by FOXO. (H) The 13 conserved FOXO/DAF‐16 targets are known to functionally regulate aging in the mouse (GenAge database).