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Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans


Chromatin modifiers regulate lifespan in several organisms, raising the question of whether changes in chromatin states in the parental generation could be incompletely reprogrammed in the next generation and thereby affect the lifespan of descendants. The histone H3 lysine 4 trimethylation (H3K4me3) complex, composed of ASH-2, WDR-5 and the histone methyltransferase SET-2, regulates Caenorhabditis elegans lifespan. Here we show that deficiencies in the H3K4me3 chromatin modifiers ASH-2, WDR-5 or SET-2 in the parental generation extend the lifespan of descendants up until the third generation. The transgenerational inheritance of lifespan extension by members of the ASH-2 complex is dependent on the H3K4me3 demethylase RBR-2, and requires the presence of a functioning germline in the descendants. Transgenerational inheritance of lifespan is specific for the H3K4me3 methylation complex and is associated with epigenetic changes in gene expression. Thus, manipulation of specific chromatin modifiers only in parents can induce an epigenetic memory of longevity in descendants.

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Figure 1: Genetically wild-type descendants from wdr-5 mutant parents have extended lifespan for several generations.
Figure 2: Genetically wild-type descendants from set-2 mutant parents have extended lifespan for several generations.
Figure 3: Knockdown of ash-2 only in the parental generation extends lifespan for several generations.
Figure 4: Transgenerational inheritance of longevity by deficiencies in ASH-2 complex members is dependent on the presence of the H3K4me3 demethylase RBR-2 and an intact germline.
Figure 5: Other longevity regulators do not have a transgenerational effect on lifespan.
Figure 6: Genetically wild-type descendants from wdr -5 mutant parents exhibit differences in gene expression, but not in global H3K4me3 levels, compared to descendants from wild-type parents.

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We are grateful to J. Lieb, A. Rechtsteiner and S. Strome for sharing their ModENCODE data pre-publication and for helpful discussion. We thank K. Shen, M. W. Tan and T. Stiernagle and the Caenorhabditis Genetics Center for gifts of strains and reagents. We thank B. Meyer for her gift of the ASH-2 antibody. We thank A. Fire, S. Kim, J. Sage, S. Iwase, J. Lipsick, E. Pollina, A. Villeneuve and members of the Brunet lab for discussions and critical reading of the manuscript. We thank S. Han for screening different H3K4me3 antibodies for western blots in worm extracts. We thank R. Liefke and H. Tang for help with microarray analysis. This work was supported by NIH R01-AG31198 grant and by a generous gift from the Glenn Foundation for Medical Research to A.B.; E.L.G. was supported by an NSF graduate fellowship, by NIH ARRA-AG31198, by T32-CA009361, by a Helen Hay Whitney Post-Doctoral fellowship, and by a NIH R01-GM058012 (to Y.S.). T.J.M. was supported by NIH F32-AG037254. J.P.L. was supported by NIH T32-MH020016.

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Authors and Affiliations



E.L.G. conceived and planned the study with the help of A.B. E.L.G. performed the experiments and wrote the paper with the help of A.B.; E.L.G. performed some of the experiments in the lab of Y.S.; T.J.M. performed immunocytochemistry experiments (Fig. 6b and Supplementary Figs 6c and 7c); D.U. performed Pvclust and PCA microarray analysis (Fig. 6d, e and Supplementary Fig. 10a, b). A.G.H. helped with Figs 3b, c and 6a and Supplementary Figs 6a, b and 7a, b. E.M. performed an independent repeat of the transgenerational wdr-5 RNAi longevity experiments (Supplementary Table 2). J.P.L. helped with Fig. 3c and Supplementary Fig. 7a, b. B.A.B. helped with bioinformatics analysis (Supplementary Table 7). All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Anne Brunet.

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The authors declare no competing financial interests.

Additional information

The raw unfiltered microarray results are deposited at the Gene Expression Omnibus (GEO) under the Subseries entry GSE31043. The raw unfiltered chromatin immunoprecipitation (ChIP)-chip data are deposited at GEO under the Subseries entry GSE30789.

Supplementary information

Supplementary Information

The file contains a Supplementary Discussion, additional references, Supplementary Figures 1-10 with legends and Supplementary Tables 1-4. (PDF 12484 kb)

Supplementary Table 5

The table shows Normalized and log-transformed microarray gene expression values of all genes from L3 stage worms collected at the first day of egg-laying. (XLS 8204 kb)

Supplementary Table 6

The table shows normalized and log-transformed microarray gene expression values of all genes from L3 stage worms collected at the second day of egg-laying. (XLS 8204 kb)

Supplementary Table 7

The table shows lists of genes regulated by WDR-5, genes with transgenerational inheritance of expression, and genes with transgenerational inheritance of expression that are expressed in the germline. (XLS 404 kb)

Supplementary Table 8

The table shows GO enrichment for WDR-5 regulated genes. (XLS 17 kb)

Supplementary Table 9

The table shows normalized and log-transformed microarray gene expression values of WDR-5 regulated genes from L3 stage worms collected at the first day of egg- laying. (XLS 3213 kb)

Supplementary Table 10

The table shows normalized and log-transformed microarray gene expression values of WDR-5 regulated genes from L3 stage worms collected at the second day of egg-laying. (XLS 644 kb)

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Greer, E., Maures, T., Ucar, D. et al. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479, 365–371 (2011).

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