title: Longevity Genes Revealed by Integrative Analysis of Isoform-Specific daf-16/FoxO Mutants of Caenorhabditis elegans.
abstract: FoxO transcription factors promote longevity across taxa. How they do so is poorly understood. In the nematode Caenorhabditis elegans, the A- and F-isoforms of the FoxO transcription factor DAF-16 extend life span in the context of reduced DAF-2 insulin-like growth factor receptor (IGFR) signaling. To elucidate the mechanistic basis for DAF-16/FoxO-dependent life span extension, we performed an integrative analysis of isoform-specific daf-16/FoxO mutants. In contrast to previous studies suggesting that DAF-16F plays a more prominent role in life span control than DAF-16A, isoform-specific daf-16/FoxO mutant phenotypes and whole transcriptome profiling revealed a predominant role for DAF-16A over DAF-16F in life span control, stress resistance, and target gene regulation. Integration of these datasets enabled the prioritization of a subset of 92 DAF-16/FoxO target genes for functional interrogation. Among 29 genes tested, two DAF-16A-specific target genes significantly influenced longevity. A loss-of-function mutation in the conserved gene gst-20, which is induced by DAF-16A, reduced life span extension in the context of daf-2/IGFR RNAi without influencing longevity in animals subjected to control RNAi. Therefore, gst-20 promotes DAF-16/FoxO-dependent longevity. Conversely, a loss-of-function mutation in srr-4, a gene encoding a seven-transmembrane-domain receptor family member that is repressed by DAF-16A, extended life span in control animals, indicating that DAF-16/FoxO may extend life span at least in part by reducing srr-4 expression. Our discovery of new longevity genes underscores the efficacy of our integrative strategy while providing a general framework for identifying specific downstream gene regulatory events that contribute substantially to transcription factor functions. As FoxO transcription factors have conserved functions in promoting longevity and may be dysregulated in aging-related diseases, these findings promise to illuminate fundamental principles underlying aging in animals.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Albert Tzong-Yang
authors.initials: AT
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Chunfang
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Omar A
authors.initials: OA
authors.lastname: Itani
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Breane G
authors.initials: BG
authors.lastname: Budaitis
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Travis W
authors.initials: TW
authors.lastname: Williams
authors.affiliation: Knudra Transgenics, Murray, Utah 84123.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Hopkins
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Richard C
authors.initials: RC
authors.lastname: McEachin
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Manjusha
authors.initials: M
authors.lastname: Pande
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Grant
authors.affiliation: Department of Physiology, Tokyo Women's Medical University School of Medicine, Tokyo, 162-8666, Japan.
authors.forename: Sawako
authors.initials: S
authors.lastname: Yoshina
authors.affiliation: Department of Physiology, Tokyo Women's Medical University School of Medicine, Tokyo, 162-8666, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Mitani
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109 Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109 Institute of Gerontology, University of Michigan Medical School, Ann Arbor, Michigan 48109 pathu@umich.edu.
authors.forename: Patrick J
authors.identifier: http://orcid.org/0000-0003-2701-9505
authors.initials: PJ
authors.lastname: Hu
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D007328:Insulin / Q000235:genetics; D008136:Longevity / Q000235:genetics*; D009154:Mutation; D020033:Protein Isoforms; D017451:Receptors, Somatomedin / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D007328:Insulin; D020033:Protein Isoforms; D017451:Receptors, Somatomedin; C108831:daf-16 protein, C elegans
keywords: C. elegans; FoxO transcription factors; aging; insulin-like growth factor signaling; longevity