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- Transcriptional regulation of Caenorhabditis elegans FOXO/DAF-16 modulates lifespan
- A Bansal; Eun Soo Kwon; D Conte; H Liu; M J Gilchrist; L T MacNeil; H A Tissenbaum
- Bibliographic Citation
- Longevity & Healthspan, vol. 3, pp. 5-5
- Publication Year
- 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.
- LongevityDAF-16/FOXOC. elegansTranscriptionAgingIsoforms
- BioMed Central
- Appears in Collections:
- Aging Convergence Research Center > 1. Journal Articles
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