A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immortality (original) (raw)

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

Subjects

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.

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

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

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

Additional access options:

Similar content being viewed by others

Accession codes

Accessions

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

Download references

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).

Author information

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

Authors

  1. Bethany A. Buckley
    You can also search for this author inPubMed Google Scholar
  2. Kirk B. Burkhart
    You can also search for this author inPubMed Google Scholar
  3. Sam Guoping Gu
    You can also search for this author inPubMed Google Scholar
  4. George Spracklin
    You can also search for this author inPubMed Google Scholar
  5. Aaron Kershner
    You can also search for this author inPubMed Google Scholar
  6. Heidi Fritz
    You can also search for this author inPubMed Google Scholar
  7. Judith Kimble
    You can also search for this author inPubMed Google Scholar
  8. Andrew Fire
    You can also search for this author inPubMed Google Scholar
  9. Scott Kennedy
    You can also search for this author inPubMed Google Scholar

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.

Corresponding author

Correspondence toScott Kennedy.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

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)

Supplementary Tables

This zipped file contains Supplementary Table 2. (ZIP 614 kb)

PowerPoint slides

Rights and permissions

About this article

Cite this article

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

Download citation

This article is cited by

Editorial Summary

Germline immortality transmitted by small RNAs

Gene silencing due to RNA-mediated interference (RNAi) in the nematode Caenorhabditis elegans can be inherited for more than five generations. Here, Scott Kennedy and colleagues have performed a genetic screen for defects in the transmission of RNAi-silencing signals to future generations, and identify a nuclear-localized Argonaute protein termed HRDE-1. It associates with small-interfering RNAs and acts in the germ cells of the progeny of animals exposed to double-stranded RNA to promote multigenerational inheritance of silencing. The authors propose that one biological function of the RNAi-inheritance machinery is to transmit ‘germline immortality’ in the form of small RNAs, selected for their ability to promote fertility, across generational boundaries.