Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes


Pseudogenes populate the mammalian genome as remnants of artefactual incorporation of coding messenger RNAs into transposon pathways1. Here we show that a subset of pseudogenes generates endogenous small interfering RNAs (endo-siRNAs) in mouse oocytes. These endo-siRNAs are often processed from double-stranded RNAs formed by hybridization of spliced transcripts from protein-coding genes to antisense transcripts from homologous pseudogenes. An inverted repeat pseudogene can also generate abundant small RNAs directly. A second class of endo-siRNAs may enforce repression of mobile genetic elements, acting together with Piwi-interacting RNAs. Loss of Dicer, a protein integral to small RNA production, increases expression of endo-siRNA targets, demonstrating their regulatory activity. Our findings indicate a function for pseudogenes in regulating gene expression by means of the RNA interference pathway and may, in part, explain the evolutionary pressure to conserve argonaute-mediated catalysis in mammals.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Both piRNA and siRNA systems control transposons in mouse oocytes.
Figure 2: Gene–pseudogene interactions produce endogenous siRNAs.
Figure 3: Endo-siRNAs have a role in gene regulation.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Small RNA data sets can be accessed in GEO with the following accession numbers GSM261957, GSM261958 and GSM261959.


  1. D’Errico, I., Gadaleta, G. & Saccone, C. Pseudogenes in metazoa: origin and features. Brief. Funct. Genomics Proteomics 3, 157–167 (2004)

    Article  Google Scholar 

  2. Aravin, A. A., Hannon, G. J. & Brennecke, J. The Piwi-piRNA pathway provides an adaptive defense in the transposon arms race. Science 318, 761–764 (2007)

    Article  ADS  CAS  Google Scholar 

  3. Aravin, A. A., Sachidanandam, R., Girard, A., Fejes-Toth, K. & Hannon, G. J. Developmentally regulated piRNA clusters implicate MILI in transposon control. Science 316, 744–747 (2007)

    Article  ADS  CAS  Google Scholar 

  4. Brennecke, J. et al. Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila . Cell 128, 1089–1103 (2007)

    Article  CAS  Google Scholar 

  5. Carmell, M. A. et al. MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. Dev. Cell 12, 503–514 (2007)

    Article  CAS  Google Scholar 

  6. Gunawardane, L. S. et al. A slicer-mediated mechanism for repeat-associated siRNA 5′ end formation in Drosophila . Science 315, 1587–1590 (2007)

    Article  ADS  CAS  Google Scholar 

  7. Houwing, S. et al. A role for Piwi and piRNAs in germ cell maintenance and transposon silencing in zebrafish. Cell 129, 69–82 (2007)

    Article  CAS  Google Scholar 

  8. Saito, K. et al. Specific association of Piwi with rasiRNAs derived from retrotransposon and heterochromatic regions in the Drosophila genome. Genes Dev. 20, 2214–2222 (2006)

    Article  CAS  Google Scholar 

  9. Vagin, V. V. et al. A distinct small RNA pathway silences selfish genetic elements in the germline. Science 313, 320–324 (2006)

    Article  ADS  CAS  Google Scholar 

  10. Kuramochi-Miyagawa, S. et al. Mili, a mammalian member of piwi family gene, is essential for spermatogenesis. Development 131, 839–849 (2004)

    Article  CAS  Google Scholar 

  11. Deng, W. & Lin, H. miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis. Dev. Cell 2, 819–830 (2002)

    Article  CAS  Google Scholar 

  12. Aravin, A. et al. A novel class of small RNAs bind to MILI protein in mouse testes. Nature 442, 203–207 (2006)

    ADS  CAS  Google Scholar 

  13. Landgraf, P. et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401–1414 (2007)

    Article  CAS  Google Scholar 

  14. Murchison, E. P. et al. Critical roles for Dicer in the female germline. Genes Dev. 21, 682–693 (2007)

    Article  CAS  Google Scholar 

  15. Allen, E., Xie, Z., Gustafson, A. M. & Carrington, J. C. microRNA-directed phasing during trans-acting siRNA biogenesis in plants. Cell 121, 207–221 (2005)

    Article  CAS  Google Scholar 

  16. Martinez, J. & Tuschl, T. RISC is a 5′ phosphomonoester-producing RNA endonuclease. Genes Dev. 18, 975–980 (2004)

    Article  CAS  Google Scholar 

  17. Schwarz, D. S., Tomari, Y. & Zamore, P. D. The RNA-induced silencing complex is a Mg2+-dependent endonuclease. Curr. Biol. 14, 787–791 (2004)

    Article  CAS  Google Scholar 

  18. Tang, F. et al. Maternal microRNAs are essential for mouse zygotic development. Genes Dev. 21, 644–648 (2007)

    Article  CAS  Google Scholar 

  19. Joshua-Tor, L. The Argonautes. Cold Spring Harb. Symp. Quant. Biol. 71, 67–72 (2006)

    Article  CAS  Google Scholar 

  20. Murchison, E. P. et al. Conservation of small RNA pathways in platypus. Genome Res. (in the press)

  21. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004)

    Article  CAS  Google Scholar 

  22. Korneev, S. A., Park, J. H. & O’Shea, M. Neuronal expression of neural nitric oxide synthase (nNOS) protein is suppressed by an antisense RNA transcribed from an NOS pseudogene. J. Neurosci. 19, 7711–7720 (1999)

    Article  CAS  Google Scholar 

  23. Weil, D., Power, M. A., Webb, G. C. & Li, C. L. Antisense transcription of a murine FGFR-3 psuedogene during fetal developement. Gene 187, 115–122 (1997)

    Article  CAS  Google Scholar 

  24. Zhou, B. S., Beidler, D. R. & Cheng, Y. C. Identification of antisense RNA transcripts from a human DNA topoisomerase I pseudogene. Cancer Res. 52, 4280–4285 (1992)

    CAS  PubMed  Google Scholar 

  25. Watanabe, T. et al. Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature doi: 10.1038/nature06908 (this issue)

  26. Stein, P., Zeng, F., Pan, H. & Schultz, R. M. Absence of non-specific effects of RNA interference triggered by long double-stranded RNA in mouse oocytes. Dev. Biol. 286, 464–471 (2005)

    Article  CAS  Google Scholar 

  27. Bettegowda, A. & Smith, G. W. Mechanisms of maternal mRNA regulation: implications for mammalian early embryonic development. Front. Biosci. 12, 3713–3726 (2007)

    Article  CAS  Google Scholar 

  28. Stitzel, M. L. & Seydoux, G. Regulation of the oocyte-to-zygote transition. Science 316, 407–408 (2007)

    Article  ADS  CAS  Google Scholar 

  29. Schultz, R. M., Montgomery, R. R. & Belanoff, J. R. Regulation of mouse oocyte meiotic maturation: implication of a decrease in oocyte cAMP and protein dephosphorylation in commitment to resume meiosis. Dev. Biol. 97, 264–273 (1983)

    Article  CAS  Google Scholar 

  30. Lee, J. S., Katari, G. & Sachidanandam, R. GObar: a gene ontology based analysis and visualization tool for gene sets. BMC Bioinformatics 6, 189 (2005)

    Article  Google Scholar 

Download references


We thank members of the Hannon laboratory for discussions. O.H.T. is a Bristol-Meyers Squibb fellow and A.G. is a Florence Gould Foundation Scholar of the Watson School of Biological Sciences. E.P.M. is supported by a fellowship from the Australian-American Association. This work was supported in part by grants from the NIH (R.M.S. and G.J.H.) and gifts from Kathryn W. Davis and the Stanley family (G.J.H. and E.H.). G.J.H. is an Investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Gregory J. Hannon.

Supplementary information

Supplementary information

The file contains Supplementary Figures S1-S5 with Legends and Supplementary Tables S1-S5. (PDF 1041 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Tam, O., Aravin, A., Stein, P. et al. Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature 453, 534–538 (2008).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing