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DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity

Nature Cell Biology volume 15, pages 491–501 (2013)Cite this article

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Abstract

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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Figure 1: DAF-16/FOXO binds to the chromatin remodeller SWI/SNF.
Figure 2: A BAF-like subclass of SWI/SNF is required for regulation of DAF-16/FOXO target genes.
Figure 3: SWI/SNF is required for regulation of a large fraction of DAF-16/FOXO target genes—in particular those activated by DAF-16/FOXO. Wild-type, daf-2(e1370ts), daf-2(e1370ts); daf-16(0), and daf-2(e1370ts); swsn-1(os22ts) C. elegans were grown to the L4 stage, and then shifted to restrictive temperature. After 20 h, genome-wide mRNA expression levels were determined by mRNA-seq.
Figure 4: SWI/SNF extensively associates with DAF-16/FOXO-bound promoter regions.
Figure 5: DAF-16/FOXO recruits SWI/SNF specifically to target promoters that are directly activated by DAF-16/FOXO.
Figure 6: SWI/SNF is required for DAF-16/FOXO-mediated dauer formation, stress resistance and longevity.

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Acknowledgements

We thank H. Sawa (National Institute of Genetics, Japan), S. Mitani (Tokyo Women’s Medical University, Japan), M. Hansen (Sanford-Burnham Medical Research Institute, USA) and the Caenorhabditis Genetics Center for strains. We thank G. Hayes, U. Kim, M. Borowski, A. Puczinska and D. Grau for experimental support. We thank I. Cheeseman, K. Bouazoune, M. Simon, B. Ardehali, W. Mair, T. Montgomery and the Avruch laboratory for helpful discussions. This work was supported by grants from the National Institutes of Health to G.R. (AG014161 and AG016636), J.M.A. (5P30CA006516 and 2P01CA120964), J.A.W. (F32GM093491), N.V.K. (F32AI100501-01) and R.E.K. (GM048405). C.G.R. was supported by long-term fellowships from the Human Frontier Science Program and the European Molecular Biology Organization, R.H.D. by the American Cancer Society (122240-PF-12-078-01-RMC), N.V.K. by a Tosteson Postdoctoral Fellowship Award, S.K.B. by the Damon Runyon Cancer Research Foundation, and T.H. by the Glenn Foundation for Medical Research and the Austrian Science Fund (FWF).

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  1. Christian G. Riedel

    Present address: Present address: European Research Institute for the Biology of Ageing, University Medical Center Groningen, 9713 AV Groningen, The Netherlands,

Authors and Affiliations

  1. Department of Molecular Biology, Massachusetts General Hospital, Massachusetts 02114, Boston, USA

    Christian G. Riedel, Robert H. Dowen, Guinevere F. Lourenco, Natalia V. Kirienko, Jason A. West, Sarah K. Bowman, Robert E. Kingston & Gary Ruvkun

  2. Department of Genetics, Harvard Medical School, Massachusetts 02114, Boston, USA

    Christian G. Riedel, Robert H. Dowen, Guinevere F. Lourenco, Natalia V. Kirienko, Jason A. West, Sarah K. Bowman, Robert E. Kingston & Gary Ruvkun

  3. Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, California 92037, La Jolla, USA

    Thomas Heimbucher & Andrew Dillin

  4. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Massachusetts 02115, Boston, USA

    John M. Asara

  5. Department of Medicine, Harvard Medical School, Massachusetts 02115, Boston, USA

    John M. Asara

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Contributions

C.G.R. and G.R. conceived and designed the experiments. C.G.R., G.F.L., N.V.K., J.A.W. and J.M.A. conducted the experiments. R.H.D. analysed the mRNA-seq and ChIP-seq data. S.K.B., R.E.K., T.H. and A.D. provided unpublished methods, materials and advice. C.G.R. and G.R. wrote the manuscript.

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Correspondence to Gary Ruvkun.

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Riedel, C., Dowen, R., Lourenco, G. et al. DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity. Nat Cell Biol 15, 491–501 (2013). https://doi.org/10.1038/ncb2720

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