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

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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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.

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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.

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Acknowledgements

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.

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Correspondence to Gregory J. Hannon.

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

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Tam, O., Aravin, A., Stein, P. et al. Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature 453, 534–538 (2008). https://doi.org/10.1038/nature06904

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