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

Nature 466, 383–387 (15 July 2010) | Download Citation

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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.

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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

Affiliations

  1. Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA

    • Eric L. Greer
    • , Travis J. Maures
    • , Anna G. Hauswirth
    • , Dena S. Leeman
    • , Shuo Han
    • , Max R. Banko
    •  & Anne Brunet

  2. Cancer Biology Graduate Program, Stanford University, Stanford, California 94305, USA

    • Eric L. Greer
    • , Dena S. Leeman
    • , Or Gozani
    •  & Anne Brunet

  3. Departments of Biology and Pathology, Stanford University, Stanford, California 94305, USA

    • Géraldine S. Maro

  4. Department of Biology, Stanford University, Stanford, California 94305, USA

    • Erin M. Green
    •  & Or Gozani

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Anne Brunet.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1-10 with legends and Supplementary Tables 1-5.

Excel files

  1. 1.

    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).

  2. 2.

    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).

  3. 3.

    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).

  4. 4.

    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).

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DOI

https://doi.org/10.1038/nature09195

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