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Longevity & Healthspan
Published in: Longevity & Healthspan 1/2014

Open Access 01-12-2014 | Research

Transcriptional regulation of Caenorhabditis elegansFOXO/DAF-16 modulates lifespan

Authors: Ankita Bansal, Eun-Soo Kwon, Darryl Conte Jr, Haibo Liu, Michael J Gilchrist, Lesley T MacNeil, Heidi A Tissenbaum

Published in: Longevity & Healthspan | Issue 1/2014

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Abstract

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.
Appendix
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Metadata
Title
Transcriptional regulation of Caenorhabditis elegansFOXO/DAF-16 modulates lifespan
Authors
Ankita Bansal
Eun-Soo Kwon
Darryl Conte Jr
Haibo Liu
Michael J Gilchrist
Lesley T MacNeil
Heidi A Tissenbaum
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Longevity & Healthspan / Issue 1/2014
Electronic ISSN: 2046-2395
DOI
https://doi.org/10.1186/2046-2395-3-5

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