Transcriptional regulation of Caenorhabditis elegans FOXO/DAF-16 modulates lifespan
Authors
Bansal, AnkitaKwon, Eun-Soo
Conte, Darryl Jr.
Liu, Haibo
Gilchrist, Michael J.
MacNeil, Lesley T.
Tissenbaum, Heidi A.
UMass Chan Affiliations
Program in Molecular MedicineProgram in Systems Biology
RNA Therapeutics Institute
Program in Gene Function and Expression
Document Type
Journal ArticlePublication Date
2014-04-23Keywords
AgingC. elegans
DAF-16/FOXO
Isoforms
Longevity
Transcription
Biochemistry
Cellular and Molecular Physiology
Genetics and Genomics
Molecular Biology
Molecular Genetics
Metadata
Show full item recordAbstract
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.Source
Bansal A, Kwon ES, Conte D Jr, Liu H, Gilchrist MJ, MacNeil LT, Tissenbaum HA. Transcriptional regulation of Caenorhabditis elegans FOXO/DAF-16 modulates lifespan. Longev Healthspan. 2014 Apr 23;3:5. doi: 10.1186/2046-2395-3-5. Link to article on publisher's siteDOI
10.1186/2046-2395-3-5Permanent Link to this Item
http://hdl.handle.net/20.500.14038/44033PubMed ID
24834345Notes
First author Ankita Bansal is a doctoral student in the Interdisciplinary Graduate Program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.
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Link to Article in PubMedRights
Copyright 2014 Bansal et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
ae974a485f413a2113503eed53cd6c53
10.1186/2046-2395-3-5