Transcriptional regulation of Caenorhabditis elegans FOXO/DAF-16 modulates lifespan

Longevity & Healthspan

Heidi A Tissenbaum⁴  Lesley T MacNeil³  Michael J Gilchrist¹  Haibo Liu²  Darryl Conte⁴  Eun-Soo Kwon⁵  Ankita Bansal² 

[1] MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, UK;Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA;Program in Systems Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA;Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA;Laboratory of Cell Signaling, Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 306-809, Korea

关键词: Isoforms;    Aging;    Transcription;    C. elegans;    DAF-16/FOXO;    Longevity;   

Others  :  802278
DOI  :  10.1186/2046-2395-3-5

 received in 2014-03-20, accepted in 2014-04-04,  发布年份 2014

【 摘 要 】

Background

Insulin/IGF-1 signaling plays a central role in longevity across phylogeny. In C. elegans, the forkhead box O (FOXO) transcription factor, DAF-16, is the primary target of insulin/IGF-1 signaling, and multiple isoforms of DAF-16 (a, b, and d/f) modulate lifespan, metabolism, dauer formation, and stress resistance. Thus far, across phylogeny modulation of mammalian FOXOs and DAF-16 have focused on post-translational regulation with little focus on transcriptional regulation. In C. elegans, we have previously shown that DAF-16d/f cooperates with DAF-16a to promote longevity. In this study, we generated transgenic strains expressing near-endogenous levels of either daf-16a or daf-16d/f, and examined temporal expression of the isoforms to further define how these isoforms contribute to lifespan regulation.

Results

Here, we show that DAF-16a is sensitive both to changes in gene dosage and to alterations in the level of insulin/IGF-1 signaling. Interestingly, we find that as worms age, the intestinal expression of daf-16d/f but not daf-16a is dramatically upregulated at the level of transcription. Preventing this transcriptional upregulation shortens lifespan, indicating that transcriptional regulation of daf-16d/f promotes longevity. In an RNAi screen of transcriptional regulators, we identify elt-2 (GATA transcription factor) and swsn-1 (core subunit of SWI/SNF complex) as key modulators of daf-16d/f gene expression. ELT-2 and another GATA factor, ELT-4, promote longevity via both DAF-16a and DAF-16d/f while the components of SWI/SNF complex promote longevity specifically via DAF-16d/f.

Conclusions

Our findings indicate that transcriptional control of C. elegans FOXO/daf-16 is an essential regulatory event. Considering the conservation of FOXO across species, our findings identify a new layer of FOXO regulation as a potential determinant of mammalian longevity and age-related diseases such as cancer and diabetes.

【 授权许可】

   
2014 Bansal et al.; licensee BioMed Central Ltd.

【 图 表 】

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