Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans

Abstract

The plasticity of ageing suggests that longevity may be controlled epigenetically by specific alterations in chromatin state. The link between chromatin and ageing has mostly focused on histone deacetylation by the Sir2 family1,2, but less is known about the role of other histone modifications in longevity. Histone methylation has a crucial role in development and in maintaining stem cell pluripotency in mammals3. Regulators of histone methylation have been associated with ageing in worms4,5,6,7 and flies8, but characterization of their role and mechanism of action has been limited. Here we identify the ASH-2 trithorax complex9, which trimethylates histone H3 at lysine 4 (H3K4), as a regulator of lifespan in Caenorhabditis elegans in a directed RNA interference (RNAi) screen in fertile worms. Deficiencies in members of the ASH-2 complex—ASH-2 itself, WDR-5 and the H3K4 methyltransferase SET-2—extend worm lifespan. Conversely, the H3K4 demethylase RBR-2 is required for normal lifespan, consistent with the idea that an excess of H3K4 trimethylation—a mark associated with active chromatin—is detrimental for longevity. Lifespan extension induced by ASH-2 complex deficiency requires the presence of an intact adult germline and the continuous production of mature eggs. ASH-2 and RBR-2 act in the germline, at least in part, to regulate lifespan and to control a set of genes involved in lifespan determination. These results indicate that the longevity of the soma is regulated by an H3K4 methyltransferase/demethylase complex acting in the C. elegans germline.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: ASH-2, WDR-5 and SET-2 function together to regulate H3K4me3 and lifespan in C. elegans.
Figure 2: RBR-2 is an H3K4me3 demethylase that counteracts the effect of the ASH-2 methyltransferase complex.
Figure 3: An intact germline is necessary for longevity and gene expression control by the H3K4me3 regulatory complex.
Figure 4: ASH-2/RBR-2 function primarily in the germline to regulate lifespan and require the continuous production of mature eggs for lifespan extension.

References

  1. Blander, G. & Guarente, L. The Sir2 family of protein deacetylases. Annu. Rev. Biochem. 73, 417–435 (2004)

    Article  CAS  PubMed  Google Scholar 

  2. Dang, W. et al. Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459, 802–807 (2009)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  3. Nottke, A., Colaiacovo, M. P. & Shi, Y. Developmental roles of the histone lysine demethylases. Development 136, 879–889 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  6. McColl, G. et al. Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans. J. Biol. Chem. 283, 350–357 (2008)

    Article  CAS  PubMed  Google Scholar 

  7. Chen, S. et al. The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span. Proc. Natl Acad. Sci. USA 106, 1496–1501 (2009)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  8. Siebold, A. P. et al. Polycomb repressive complex 2 and trithorax modulate Drosophila longevity and stress resistance. Proc. Natl Acad. Sci. USA 107, 169–174 (2010)

    Article  CAS  ADS  PubMed  Google Scholar 

  9. Wysocka, J., Myers, M. P., Laherty, C. D., Eisenman, R. N. & Herr, W. Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3–K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1. Genes Dev. 17, 896–911 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lee, S. S. et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nature Genet. 33, 40–48 (2003)

    Article  CAS  PubMed  Google Scholar 

  11. Hansen, M., Hsu, A. L., Dillin, A. & Kenyon, C. New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen. PLoS Genet. 1, e17 (2005)

    Article  PubMed Central  Google Scholar 

  12. Miller, T. et al. COMPASS: a complex of proteins associated with a trithorax-related SET domain protein. Proc. Natl Acad. Sci. USA 98, 12902–12907 (2001)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  13. Papoulas, O. et al. The Drosophila trithorax group proteins BRM, ASH1 and ASH2 are subunits of distinct protein complexes. Development 125, 3955–3966 (1998)

    CAS  PubMed  Google Scholar 

  14. Dou, Y. et al. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nature Struct. Mol. Biol. 13, 713–719 (2006)

    Article  CAS  Google Scholar 

  15. Wysocka, J. et al. WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development. Cell 121, 859–872 (2005)

    Article  CAS  PubMed  Google Scholar 

  16. Simonet, T., Dulermo, R., Schott, S. & Palladino, F. Antagonistic functions of SET-2/SET1 and HPL/HP1 proteins in C. elegans development. Dev. Biol. 312, 367–383 (2007)

    Article  CAS  PubMed  Google Scholar 

  17. Ruthenburg, A. J., Allis, C. D. & Wysocka, J. Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol. Cell 25, 15–30 (2007)

    Article  CAS  PubMed  Google Scholar 

  18. Schneider, J. et al. Molecular regulation of histone H3 trimethylation by COMPASS and the regulation of gene expression. Mol. Cell 19, 849–856 (2005)

    Article  CAS  PubMed  Google Scholar 

  19. Christensen, J. et al. RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell 128, 1063–1076 (2007)

    Article  CAS  PubMed  Google Scholar 

  20. Xu, L. & Strome, S. Depletion of a novel SET-domain protein enhances the sterility of mes-3 and mes-4 mutants of Caenorhabditis elegans. Genetics 159, 1019–1029 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Arantes-Oliveira, N., Apfeld, J., Dillin, A. & Kenyon, C. Regulation of life-span by germ-line stem cells in Caenorhabditis elegans. Science 295, 502–505 (2002)

    Article  CAS  ADS  PubMed  Google Scholar 

  22. Berman, J. R. & Kenyon, C. Germ-cell loss extends C. elegans life span through regulation of DAF-16 by kri-1 and lipophilic-hormone signaling. Cell 124, 1055–1068 (2006)

    Article  CAS  PubMed  Google Scholar 

  23. Budovskaya, Y. V. et al. An elt-3/elt-5/elt-6 GATA transcription circuit guides aging in C. elegans. Cell 134, 291–303 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sijen, T. et al. On the role of RNA amplification in dsRNA-triggered gene silencing. Cell 107, 465–476 (2001)

    Article  CAS  PubMed  Google Scholar 

  25. Kelly, W. G., Xu, S., Montgomery, M. K. & Fire, A. Distinct requirements for somatic and germline expression of a generally expressed Caenorhabditis elegans gene. Genetics 146, 227–238 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Mitchell, D. H., Stiles, J. W., Santelli, J. & Sanadi, D. R. Synchronous growth and aging of Caenorhabditis elegans in the presence of fluorodeoxyuridine. J. Gerontol. 34, 28–36 (1979)

    Article  CAS  PubMed  Google Scholar 

  27. Lee, S. S., Kennedy, S., Tolonen, A. C. & Ruvkun, G. DAF-16 target genes that control C. elegans life-span and metabolism. Science 300, 644–647 (2003)

    Article  CAS  ADS  PubMed  Google Scholar 

  28. Haag, E. S., Wang, S. & Kimble, J. Rapid coevolution of the nematode sex-determining genes fem-3 and tra-2. Curr. Biol. 12, 2035–2041 (2002)

    Article  CAS  PubMed  Google Scholar 

  29. Gerisch, B., Weitzel, C., Kober-Eisermann, C., Rottiers, V. & Antebi, A. A hormonal signaling pathway influencing C. elegans metabolism, reproductive development, and life span. Dev. Cell 1, 841–851 (2001)

    Article  CAS  PubMed  Google Scholar 

  30. Greer, E. L. et al. An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr. Biol. 17, 1646–1656 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mello, C. C. et al. The PIE-1 protein and germline specification in C. elegans embryos. Nature 382, 710–712 (1996)

    Article  CAS  ADS  PubMed  Google Scholar 

  32. Fire, A., Harrison, S. W. & Dixon, D. A modular set of lacZ fusion vectors for studying gene expression in Caenorhabditis elegans. Gene 93, 189–190 (1990)

    Article  CAS  PubMed  Google Scholar 

  33. Cheeseman, I. M. et al. A conserved protein network controls assembly of the outer kinetochore and its ability to sustain tension. Genes Dev. 18, 2255–2268 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Venteicher, A. S., Meng, Z., Mason, P. J., Veenstra, T. D. & Artandi, S. E. Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly. Cell 132, 945–957 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Klassen, M. P. & Shen, K. Wnt signaling positions neuromuscular connectivity by inhibiting synapse formation in C. elegans. Cell 130, 704–716 (2007)

    Article  CAS  PubMed  Google Scholar 

  36. Praitis, V., Casey, E., Collar, D. & Austin, J. Creation of low-copy integrated transgenic lines in Caenorhabditis elegans. Genetics 157, 1217–1226 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Merritt, C. & Seydoux, G. In WormBook (ed. The C. elegans Research Community). 10.1895/wormbook.1.148.1 〈http://www.wormbook.org/〉 (2010)

  38. Tusher, V. G., Tibshirani, R. & Chu, G. Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl Acad. Sci. USA 98, 5116–5121 (2001)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  39. Eisen, M. B., Spellman, P. T., Brown, P. O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl Acad. Sci. USA 95, 14863–14868 (1998)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  40. Saldanha, A. J. Java Treeview–extensible visualization of microarray data. Bioinformatics 20, 3246–3248 (2004)

    Article  CAS  PubMed  Google Scholar 

  41. Beissbarth, T. & Speed, T. P. GOstat: find statistically overrepresented Gene Ontologies within a group of genes. Bioinformatics 20, 1464–1465 (2004)

    Article  CAS  PubMed  Google Scholar 

  42. Shi, X. et al. Modulation of p53 function by SET8-mediated methylation at lysine 382. Mol. Cell 27, 636–646 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to A. Fire, K. Helin, S. Kim, K. Shen, T. Stiernagle and the Caenorhabditis Genetics Center, M. W. Tan and A. Villeneuve for gifts of strains, reagents and antibodies. We thank S. Kim, G. Seydoux, C. Slightam and K. Shen for advice on worm transgenesis, and S. Kim, A. Morgan and Y. Kobayashi for help with microarray analysis. We thank A. Fire, S. Kim, G. Seydoux, M. W. Tan and J. Wysocka for discussions. We thank members of the Brunet laboratory, M. Kaeberlein, J. Lieberman, J. Sage and J. Wysocka for critical reading of the manuscript. This work was supported by NIH grant R01-AG31198 to A.B.; E.L.G. was supported by NIH training grant T32-CA009302, an NSF graduate fellowship and by NIH ARRA-AG31198. T.J.M. was supported by NIH grant T32-HG000044. D.S.L. and E.M.G. were supported by NIH training grant T32-CA009302. S.H. was supported by a Stanford graduate fellowship. G.S.M. was supported by a Human Frontier Science Program post-doctoral fellowship. M.R.B. was supported by NIH fellowship F31-AG032837. O.G. was supported by a Searle Scholar award.

Author information

Authors and Affiliations

Authors

Contributions

E.L.G. and A.B. conceived and planned the study. E.L.G. performed the experiments and wrote the paper with the help of A.B.; T.J.M. completed Fig. 3a, b, Supplementary Fig. 4c, e and Supplementary Fig. 8c, and generated all low-copy integrant transgenic worm lines. A.G.H. helped with Fig. 1b, e and Supplementary Fig. 1f. E.M.G. was advised by O.G. and completed Fig. 1f and Supplementary Fig. 1g. D.S.L. helped with Fig. 2a. G.S.M. generated all high-copy transgenic worm lines. S.H. helped with Supplementary Fig. 8c. M.R.B. generated the Prbr-2::rbr-2::gfp construct. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Anne Brunet.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-10 with legends and Supplementary Tables 1-5. (PDF 17564 kb)

Supplementary Table 6

This table shows the normalized and log-transformed microarray gene expression values in WT(N2) and glp-1(e2141ts) mutant worms treated with empty vector (E.V.) vs ash-2 RNAi at day 2 of life (larval stage L3). (XLS 6370 kb)

Supplementary Table 7

This table shows the normalized and log-transformed microarray gene expression values in WT(N2) and glp-1(e2141ts) mutant worms treated with empty vector (E.V.) vs ash-2 RNAi at day 8 of life (day 5 of adulthood). (XLS 5970 kb)

Supplementary Table 8

This table shows the normalized microarray gene expression values at day 2 of life (larval stage L3) corresponding to the cluster in Figure 3e (left panel). (XLS 45 kb)

Supplementary Table 9

This table shows the normalized microarray gene expression values at day 8 of life (day 5 of adulthood) corresponding to the cluster in Figure 3e (right panel). (XLS 102 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Greer, E., Maures, T., Hauswirth, A. et al. Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 466, 383–387 (2010). https://doi.org/10.1038/nature09195

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09195

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing