Critical Genes Regulated by FoxO Transcription Factors in Life Span Control

[摘要] FoxO transcription factors (TFs) control metabolism, development, and aging in diverse species. Mouse models implicate FoxO dysregulation in the pathogenesis of age-related disease, including type 2 diabetes, cancer, osteoporosis, and cardiovascular disease. In the nematode C. elegans, the FoxO ortholog DAF-16 extends life span more than 2-fold in response to reduced signaling from the insulin-like growth factor receptor (IGFR) ortholog DAF-2. However, DAF-16/FoxO regulates numerous target genes, posing a significant challenge to understanding the mechanistic details of life span extension.Here, we have developed a logical framework to prioritize functional testing of DAF-16/FoxO target genes highly associated with longevity. Multiple DAF-16/FoxO isoforms are expressed in C. elegans, and we dissected the contributions of individual isoforms to life span control using novel isoform-specific daf-16/FoxO mutants. Whole-transcriptome profiling (RNA-seq) revealed the sets of target genes regulated by each DAF-16/FoxO isoform. An integrative analysis of the life span phenotypes and gene expression profiles of daf-16/FoxO isoform-specific mutants yielded an experimentally tractable list of high-priority genes likely to influence life span. We then screened these genes using a novel method and discovered critical longevity targets of DAF-16/FoxO. These findings suggest that a small subset of DAF-16/FoxO target genes may play a disproportionate role in life span control. Furthermore, most of the genes we identified are conserved in humans and may be involved in human age-related disease. Our approach integrating genetics, phenotypic analysis, and gene expression profiling may be generally useful in dissecting the mechanisms by which transcription factors influence complex processes like aging.

[发布机构] University of Michigan

[效力级别] genetics

[关键词] aging;genetics;longevity;Molecular;Cellular and Developmental Biology;Science;Cellular & Molec Biology PhD