UMMS Affiliation
Program in Gene Function and Expression; RNA Therapeutics Institute; Program in Systems Biology; Program in Molecular Medicine
Publication Date
2014-04-23
Document Type
Article
Disciplines
Biochemistry | Cellular and Molecular Physiology | Genetics and Genomics | Molecular Biology | Molecular Genetics
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.
Keywords
Aging, C. elegans, DAF-16/FOXO, Isoforms, Longevity, Transcription
Rights and Permissions
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.
DOI of Published Version
10.1186/2046-2395-3-5
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 site
Journal/Book/Conference Title
Longevity and healthspan
Related Resources
PubMed ID
24834345
Repository Citation
Bansal, Ankita; Kwon, Eun-Soo; Conte, Darryl Jr.; Liu, Haibo; Gilchrist, Michael J.; MacNeil, Lesley T.; and Tissenbaum, Heidi A., "Transcriptional regulation of Caenorhabditis elegans FOXO/DAF-16 modulates lifespan" (2014). Program in Gene Function and Expression Publications and Presentations. 248.
https://escholarship.umassmed.edu/pgfe_pp/248
Included in
Biochemistry Commons, Cellular and Molecular Physiology Commons, Molecular Biology Commons, Molecular Genetics Commons
Comments
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.