Nature 453, 534-538 (22 May 2008) | doi:10.1038/nature06904; Received 1 November 2007; Accepted 7 March 2008; Published online 10 April 2008

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

Oliver H. Tam1,3, Alexei A. Aravin1,3, Paula Stein2, Angelique Girard1, Elizabeth P. Murchison1, Sihem Cheloufi1, Emily Hodges1, Martin Anger2,4, Ravi Sachidanandam1, Richard M. Schultz2 & Gregory J. Hannon1

  1. Cold Spring Harbor Laboratory, Watson School of Biological Sciences and Howard Hughes Medical Institute, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA
  2. Department of Biology, University of Pennsylvania, 433 South University Avenue, 205 Lynch Laboratories, Philadelphia, Pennsylvania 19104-6018, USA
  3. These authors contributed equally to this work.
  4. Present address: University of Oxford, Department of Biochemistry, South Parks Road, Oxford OX1 3QU, UK.

Correspondence to: Gregory J. Hannon1 Correspondence and requests for materials should be addressed to G.J.H. (Email: hannon@cshl.edu).

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.


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