Transcriptional regulation of Caenorhabditis elegans FOXO/DAF-16 modulates lifespan
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- 作者：Ankita Bansal (1)
Eun-Soo Kwon (1) (2)
Darryl Conte Jr (3) (6)
Haibo Liu (1)
Michael J Gilchrist (4)
Lesley T MacNeil (5)
Heidi A Tissenbaum (1) (6)
1. Program in Gene Function and Expression ; University of Massachusetts Medical School ; Worcester ; MA ; 01605 ; USA
2. Laboratory of Cell Signaling ; Aging Research Center ; Korea Research Institute of Bioscience and Biotechnology ; 125 Gwahak-ro ; Yuseong-gu ; Daejeon ; 306-809 ; Korea
3. RNA Therapeutics Institute ; University of Massachusetts Medical School ; Worcester ; MA ; 01605 ; USA
6. Program in Molecular Medicine ; University of Massachusetts Medical School ; Worcester ; MA ; 01605 ; USA
4. MRC National Institute for Medical Research ; The Ridgeway ; Mill Hill ; London ; UK
5. Program in Systems Biology ; University of Massachusetts Medical School ; Worcester ; MA ; 01605 ; USA - 关键词：Longevity ; DAF ; 16/FOXO ; C. elegans ; Transcription ; Aging ; Isoforms
- 刊名：Longevity & Healthspan
- 出版年：2014
- 出版时间：December 2014
- 年：2014
- 卷：3
- 期：1
- 全文大小：1,312 KB
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- 出版者：BioMed Central
- ISSN：2046-2395
文摘
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.