Article | Published:

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

Nature Cell Biology volume 15, pages 491501 (2013) | Download Citation

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Primary accessions

Sequence Read Archive

Referenced accessions

Gene Expression Omnibus

References

  1. 1.

    The plasticity of ageing: insights from long-lived mutants. Cell 120, 449–460 (2005).

  2. 2.

    & The FoxO code. Oncogene 27, 2276–2288 (2008).

  3. 3.

    et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424, 277–283 (2003).

  4. 4.

    et al. Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project. Science 330, 1775–1787 (2010).

  5. 5.

    , , & C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span. Cell 125, 1165–1177 (2006).

  6. 6.

    , & Gene activities that mediate increased life span of C. elegans insulin-like signalling mutants. Genes Dev. 21, 2976–2994 (2007).

  7. 7.

    & Epigenetic regulation of ageing stem cells. Oncogene 30, 3105–3126 (2011).

  8. 8.

    , & Molecular chaperones in protein folding and proteostasis. Nature 475, 324–332 (2011).

  9. 9.

    et al. Barrier to autointegration factor blocks premature cell fusion and maintains adult muscle integrity in C. elegans. J. Cell Biol. 178, 661–673 (2007).

  10. 10.

    & Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genet. 3, e56 (2007).

  11. 11.

    & Unwinding chromatin for development and growth: a few genes at a time. Trends Genet. 23, 403–412 (2007).

  12. 12.

    & ATP-dependent chromatin remodelling: genetics, genomics and mechanisms. Cell Res. 21, 396–420 (2011).

  13. 13.

    , , & Reconstitution of a core chromatin remodelling complex from SWI/SNF subunits. Mol. Cell 3, 247–253 (1999).

  14. 14.

    , , & Functional differentiation of SWI/SNF remodelers in transcription and cell cycle control. Mol. Cell. Biol. 27, 651–661 (2007).

  15. 15.

    , , , & Multiple functions of PBRM-1/Polybromo- and LET-526/Osa-containing chromatin remodelling complexes in C. elegans development. Dev. Biol. 361, 349–357 (2012).

  16. 16.

    et al. Dissecting the regulatory circuitry of a eukaryotic genome. Cell 95, 717–728 (1998).

  17. 17.

    , & Components of the SWI/SNF complex are required for asymmetric cell division in C. elegans. Mol. Cell 6, 617–624 (2000).

  18. 18.

    , & Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell 115, 489–502 (2003).

  19. 19.

    & daf-16 integrates developmental and environmental inputs to mediate ageing in the nematode Caenorhabditis elegans. Curr. Biol. 11, 1975–1980 (2001).

  20. 20.

    , & Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans. Proc. Natl Acad. Sci. 104, 19046–19050 (2007).

  21. 21.

    et al. The Trithorax-like gene encodes the Drosophila GAGA factor. Nature 371, 806–808 (1994).

  22. 22.

    & Promoter targeting and chromatin remodelling by the SWI/SNF complex. Curr. Opin. Genet. Dev. 10, 187–192 (2000).

  23. 23.

    & C. elegans dauer formation and the molecular basis of plasticity. Genes Dev. 22, 2149–2165 (2008).

  24. 24.

    , , & DAF-16 target genes that control C. elegans life-span and metabolism. Science 300, 644–647 (2003).

  25. 25.

    & Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 25, 2227–2241 (2011).

  26. 26.

    & Chromatin opening and stable perturbation of core histone: DNA contacts by FoxO1. J. Biol. Chem. 282, 35583–35593 (2007).

  27. 27.

    et al. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479, 365–371 (2011).

  28. 28.

    et al. Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 466, 383–387 (2010).

  29. 29.

    & Sirtuins in ageing and age-related disease. Cell 126, 257–268 (2006).

  30. 30.

    et al. Histone H3 tail acetylation modulates ATP-dependent remodelling through multiple mechanisms. Nucleic Acids Res. 39, 8378–8391 (2011).

  31. 31.

    et al. Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc. Natl Acad. Sci. USA 106, 2700–2705 (2009).

  32. 32.

    et al. FOXO3A genotype is strongly associated with human longevity. Proc. Natl Acad. Sci. USA 105, 13987–13992 (2008).

  33. 33.

    Maintenance of C. elegans. WormBook1–11 (2006).

  34. 34.

    Reverse genetics. WormBook1–43 (2006).

  35. 35.

    et al. Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library. Genome Res. 14, 2162–2168 (2004).

  36. 36.

    et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421, 231–237 (2003).

  37. 37.

    et al. ProLuCID, a fast and sensitive tandem mass spectra-based protein identification program. Mol. Cell. Proteomics 5, S174 (2006).

  38. 38.

    , & DTASelect and Contrast: tools for assembling and comparing protein identifications from shotgun proteomics. J. Proteome Res. 1, 21–26 (2002).

  39. 39.

    et al. A systematic RNAi screen for longevity genes in C. elegans. Genes Dev. 19, 1544–1555 (2005).

  40. 40.

    , , & A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants. Nature 459, 1079–1084 (2009).

  41. 41.

    , , , & Selection and validation of a set of reliable reference genes for quantitative sod gene expression analysis in C. elegans. BMC Mol. Biol. 9, 9 (2008).

  42. 42.

    et al. Caenorhabditis elegans HCF-1 functions in longevity maintenance as a DAF-16 regulator. PLoS Biol. 6, e233 (2008).

  43. 43.

    et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456, 53–59 (2008).

  44. 44.

    , & TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009).

  45. 45.

    et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat. Biotechnol. 28, 511–515 (2010).

  46. 46.

    , , & Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).

  47. 47.

    et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).

  48. 48.

    et al. Diverse transcription factor binding features revealed by genome-wide ChIP-seq in C. elegans. Genome Res. 21, 245–254 (2011).

  49. 49.

    , , & A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19, 185–193 (2003).

  50. 50.

    et al. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 482, 221–225 (2012).

  51. 51.

    & BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010).

  52. 52.

    et al. A complete workflow for the analysis of full-size ChIP-seq (and similar) data sets using peak-motifs. Nat. Protoc. 7, 1551–1568 (2012).

  53. 53.

    & The dauer larva, a post-embryonic developmental variant of the nematode Caenorhabditis elegans. Dev. Biol. 46, 326–342 (1975).

  54. 54.

    et al. The evolutionarily conserved longevity determinants HCF-1 andSIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. PLoS Genet. 7, e1002235 (2011).

  55. 55.

    R Development Core Team R: A language and environment for statistical computing. (2010). at .

Download references

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).

Author information

Author notes

    • Christian G. Riedel

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

Affiliations

  1. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, 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, Boston, Massachusetts 02114, 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, La Jolla, California 92037, USA

    • Thomas Heimbucher
    •  & Andrew Dillin
  4. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA

    • John M. Asara
  5. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA

    • John M. Asara

Authors

  1. Search for Christian G. Riedel in:

  2. Search for Robert H. Dowen in:

  3. Search for Guinevere F. Lourenco in:

  4. Search for Natalia V. Kirienko in:

  5. Search for Thomas Heimbucher in:

  6. Search for Jason A. West in:

  7. Search for Sarah K. Bowman in:

  8. Search for Robert E. Kingston in:

  9. Search for Andrew Dillin in:

  10. Search for John M. Asara in:

  11. Search for Gary Ruvkun in:

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Gary Ruvkun.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary Information

Excel files

  1. 1.

    Supplementary Information

    Supplementary Table 1

  2. 2.

    Supplementary Information

    Supplementary Table 2

  3. 3.

    Supplementary Information

    Supplementary Table 3

  4. 4.

    Supplementary Information

    Supplementary Table 4

  5. 5.

    Supplementary Information

    Supplementary Table 5

  6. 6.

    Supplementary Information

    Supplementary Table 6

  7. 7.

    Supplementary Information

    Supplementary Table 7

  8. 8.

    Supplementary Information

    Supplementary Table 8

  9. 9.

    Supplementary Information

    Supplementary Table 9

  10. 10.

    Supplementary Information

    Supplementary Table 10

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ncb2720