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A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immortality

Nature volume 489, pages 447–451 (2012)Cite this article

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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

Data deposits

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

References

  1. Reik, W., Dean, W. & Walter, J. Epigenetic reprogramming in mammalian development. Science 293, 1089–1093 (2001)

    Article  CAS  Google Scholar 

  2. Jablonka, E. & Raz, G. Transgenerational epigenetic inheritance: prevalence, mechanisms, and implications for the study of heredity and evolution. Q. Rev. Biol. 84, 131–176 (2009)

    Article  Google Scholar 

  3. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998)

    Article  CAS  ADS  Google Scholar 

  4. Grishok, A., Tabara, H. & Mello, C. C. Genetic requirements for inheritance of RNAi in C. elegans. Science 287, 2494–2497 (2000)

    Article  CAS  ADS  Google Scholar 

  5. Vastenhouw, N. L. et al. Gene expression: long-term gene silencing by RNAi. Nature 442, 882 (2006)

    Article  CAS  ADS  Google Scholar 

  6. Alcazar, R. M., Lin, R. & Fire, A. Z. Transmission dynamics of heritable silencing induced by double-stranded RNA in Caenorhabditis elegans. Genetics 180, 1275–1288 (2008)

    Article  CAS  Google Scholar 

  7. Burton, N. O., Burkhart, K. B. & Kennedy, S. Nuclear RNAi maintains heritable gene silencing in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 108, 19683–19688 (2011)

    Article  CAS  ADS  Google Scholar 

  8. Gu, S. G., Pak, J., Guang, S., Maniar, J. M., Kennedy, S. & Fire, A. Amplification of siRNA in Caenorhabditis elegans generates a transgenerational sequence-targeted histone H3 lysine 9 methylation footprint. Nature Genet. 44, 157–164 (2012)

    Article  CAS  Google Scholar 

  9. Yigit, E. et al. Analysis of the C. elegans Argonaute family reveals that distinct Argonautes act sequentially during RNAi. Cell 127, 747–757 (2006)

    Article  CAS  Google Scholar 

  10. Gu, W. et al. Distinct argonaute-mediated 22G-RNA pathways direct genome surveillance in the C. elegans germline. Mol. Cell 36, 231–244 (2009)

    Article  CAS  Google Scholar 

  11. Guang, S. et al. An Argonaute transports siRNAs from the cytoplasm to the nucleus. Science 321, 537–541 (2008)

    Article  CAS  ADS  Google Scholar 

  12. Guang, S. et al. Small regulatory RNAs inhibit RNA polymerase II during the elongation phase of transcription. Nature 465, 1097–1101 (2010)

    Article  CAS  ADS  Google Scholar 

  13. Burkhart, K. B. et al. A pre-mRNA-associating factor links endogenous siRNAs to chromatin regulation. PLoS Genet. 7, e1002249 (2011)

    Article  CAS  Google Scholar 

  14. Beanan, M. J. & Strome, S. Characterization of a germ-line proliferation mutation in C. elegans. Development 116, 755–766 (1992)

    CAS  PubMed  Google Scholar 

  15. Pak, J. & Fire, A. Distinct populations of primary and secondary effectors during RNAi in C. elegans. Science 315, 241–244 (2007)

    Article  CAS  ADS  Google Scholar 

  16. Ahmed, S. & Hodgkin, J. MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. elegans. Nature 403, 159–164 (2000)

    Article  CAS  ADS  Google Scholar 

  17. Tabara, H. et al. The rde-1 gene, RNA interference, and transposon silencing in C. elegans. Cell 99, 123–132 (1999)

    Article  CAS  Google Scholar 

  18. Tabara, H., Yigit, E., Siomi, H. & Mello, C. C. The dsRNA binding protein RDE-4 interacts with RDE-1, DCR-1, and a DExH-box helicase to direct RNAi in C. elegans. Cell 109, 861–871 (2002)

    Article  CAS  Google Scholar 

  19. Bagijn, M. P. et al. Function, targets, and evolution of Caenorhabditis elegans piRNAs. Science http://dx.doi.org/10.1126/science.1220952 (4 June 2012)

    Google Scholar 

  20. Ashe, A. et al. piRNAs can trigger a multigenerational epigenetic memory in the germline of C. elegans.. Cell 150, 88–99 (2012)

    Article  CAS  Google Scholar 

  21. Shirayama, M. et al. piRNAs initiate an epigenetic memory of nonself RNA in the C. elegans germline. Cell 150, 65–77 (2012)

    Article  CAS  Google Scholar 

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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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Author notes

  1. Bethany A. Buckley and Kirk B. Burkhart: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Genetics, University of Wisconsin-Madison, Madison, 53706, Wisconsin, USA

    Bethany A. Buckley, Kirk B. Burkhart, George Spracklin, Heidi Fritz, Judith Kimble & Scott Kennedy

  2. Departments of Pathology and Genetics, Stanford University, Stanford, 94305, California, USA

    Sam Guoping Gu & Andrew Fire

  3. and Department of Biochemistry, Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, 53706, Wisconsin, USA

    Aaron Kershner & Judith Kimble

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Contributions

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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The authors declare no competing financial interests.

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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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