Transcriptional regulation of Caenorhabditis elegans FOXO/DAF-16 modulates lifespan.
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.
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Ankita
A
Bansal
Program in Gene Function and Expression, 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.
Eun-Soo
ES
Kwon
RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.|Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Darryl
D
Conte
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Haibo
H
Liu
MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, UK.
Michael J
MJ
Gilchrist
Program in Systems Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Lesley T
LT
MacNeil
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA.|Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Heidi A
HA
Tissenbaum
Aging; C. elegans; DAF-16/FOXO; Isoforms; Longevity; Transcription