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A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immortality

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Abstract

Epigenetic information is frequently erased near the start of each new generation1. In some cases, however, epigenetic information can be transmitted from parent to progeny (multigenerational epigenetic inheritance)2. A particularly notable example of this type of epigenetic inheritance is double-stranded RNA-mediated gene silencing in Caenorhabditis elegans. This RNA-mediated interference (RNAi) can be inherited for more than five generations3,4,5,6,7,8. To understand this process, here we conduct a genetic screen for nematodes defective in transmitting RNAi silencing signals to future generations. This screen identified the heritable RNAi defective 1 (hrde-1) gene. hrde-1 encodes an Argonaute protein that associates with small interfering RNAs in the germ cells of progeny of animals exposed to double-stranded RNA. In the nuclei of these germ cells, HRDE-1 engages the nuclear RNAi defective pathway to direct the trimethylation of histone H3 at Lys 9 (H3K9me3) at RNAi-targeted genomic loci and promote RNAi inheritance. Under normal growth conditions, HRDE-1 associates with endogenously expressed short interfering RNAs, which direct nuclear gene silencing in germ cells. In hrde-1- or nuclear RNAi-deficient animals, germline silencing is lost over generational time. Concurrently, these animals exhibit steadily worsening defects in gamete formation and function that ultimately lead to sterility. These results establish that the Argonaute protein HRDE-1 directs gene-silencing events in germ-cell nuclei that drive multigenerational RNAi inheritance and promote immortality of the germ-cell lineage. We propose that C. elegans use the RNAi inheritance machinery to transmit epigenetic information, accrued by past generations, into future generations to regulate important biological processes.

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Figure 1: hrde-1 encodes a nuclear AGO protein that acts in inheriting generations to promote multigenerational germline RNAi inheritance.
Figure 2: HRDE-1 engages the NRDE nuclear RNAi pathway to direct multigenerational RNAi inheritance.
Figure 3: The RNAi inheritance machinery transmits endogenous epigenetic information across generations.
Figure 4: The RNAi inheritance machinery promotes germline immortality.

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Gene Expression Omnibus

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ChIP-seq and hrde-1 siRNA data have been submitted to the Gene Expression Omnibus (GEO) under accession number GSE38041.

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Acknowledgements

We thank P. Anderson, H. Opalicious and D. Wassarman for discussions. We thank S. Ahmed and members of the Ahmed laboratory for sharing unpublished data concerning the role of nrde-1 in germline immortality. This work was supported by grants from the Pew and Shaw scholar’s programs, and the National Institutes of Health, GM88289 (S.K.), GM37706 (A.F.) and GM069454 (J.K).

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B.B. contributed to Figs 1a–c, 2b–d and Supplementary Figs 3, 4, 5b, 6, 8, 10 and 13. K.B. contributed to Figs 2c, 3d–f, 4a, b and Supplementary Figs 13–15, 16a–c, 17, 18 and 19c. S.G.G. and A.F. contributed to Fig. 3a–c, Supplementary Table 2 and Supplementary Figs 11 and 12. G.S. contributed to Supplementary Figs 2, 5a and 16d. A.K. and J.K contributed to Fig. 4b and Supplementary Figs 7 and 19a. H.F. contributed to Fig. 4a and Supplementary Figs 16a–c, 17, 18 and 19c. S.K. contributed to Figs 1a–d, 2a, 3b, Supplementary Table 1 and Supplementary Figs 2, 6b, 9, 10b and 19b. S.K., B.B. and K.B. wrote the manuscript.

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Correspondence to Scott Kennedy.

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This file contains a Supplementary Discussion, Supplementary Tables 1-2 (see separate zipped excel file for Supplementary Table 2), Supplementary Figures 1-19, Supplementary Material and Methods and additional references. (PDF 8332 kb)

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Buckley, B., Burkhart, K., Gu, S. et al. A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immortality. Nature 489, 447–451 (2012). https://doi.org/10.1038/nature11352

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