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).

Abstract

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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