RRC ID 45669
著者 Chen AT, Guo C, Itani OA, Budaitis BG, Williams TW, Hopkins CE, McEachin RC, Pande M, Grant AR, Yoshina S, Mitani S, Hu PJ.
タイトル Longevity Genes Revealed by Integrative Analysis of Isoform-Specific daf-16/FoxO Mutants of Caenorhabditis elegans.
ジャーナル Genetics
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.
巻・号 201(2)
ページ 613-29
公開日 2015-10-1
DOI 10.1534/genetics.115.177998
PII genetics.115.177998
PMID 26219299
PMC PMC4596673
MeSH Aging / genetics* Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / growth & development* Caenorhabditis elegans Proteins / biosynthesis Caenorhabditis elegans Proteins / genetics* Forkhead Transcription Factors / biosynthesis Forkhead Transcription Factors / genetics* Gene Expression Regulation, Developmental Insulin / genetics Longevity / genetics* Mutation Protein Isoforms Receptors, Somatomedin / genetics Signal Transduction / genetics Transcription, Genetic*
IF 4.015
引用数 30
WOS 分野 GENETICS & HEREDITY
リソース情報
線虫 tm5030 tm5032 tm6659