期刊
NATURE CELL BIOLOGY
卷 15, 期 5, 页码 491-+出版社
NATURE PORTFOLIO
DOI: 10.1038/ncb2720
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资金
- National Institutes of Health [AG014161, AG016636, 5P30CA006516, 2P01CA120964, F32GM093491, F32AI100501-01, GM048405]
- Human Frontier Science Program
- European Molecular Biology Organization
- American Cancer Society [122240-PF-12-078-01-RMC]
- Tosteson Postdoctoral Fellowship Award
- Damon Runyon Cancer Research Foundation
- Glenn Foundation for Medical Research
- Austrian Science Fund (FWF)
Organisms are constantly challenged by stresses and privations and require adaptive responses for their survival. The forkhead box O (FOXO) transcription factor DAF-16 (hereafter referred to as DAF-16/FOXO) is a central nexus in these responses, but despite its importance little is known about how it regulates its target genes. Proteomic identification of DAF-16/FOXO-binding partners in Caenorhabditis elegans and their subsequent functional evaluation by RNA interference revealed several candidate DAF-16/FOXO cofactors, most notably the chromatin remodeller SWI/SNF. DAF-16/FOXO and SWI/SNF form a complex and globally co-localize at DAF-16/FOXO target promoters. We show that specifically for gene activation, DAF-16/FOXO depends on SWI/SNF, facilitating SWI/SNF recruitment to target promoters, to activate transcription by presumed remodelling of local chromatin. For the animal, this translates into an essential role for SWI/SNF in DAF-16/FOXO-mediated processes, in particular dauer formation, stress resistance and the promotion of longevity. Thus, we give insight into the mechanisms of DAF-16/FOXO-mediated transcriptional regulation and establish a critical link between ATP-dependent chromatin remodelling and lifespan regulation.
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