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PLoS Genet. 2013 Nov;9(11):e1003791. doi: 10.1371/journal.pgen.1003791. Epub 2013 Nov 7.

RNAi-dependent and independent control of LINE1 accumulation and mobility in mouse embryonic stem cells.

Author information

1
Swiss Federal Institute of Technology Zurich, Department of Biology, Chair of RNA biology, Zurich, Switzerland ; Institut Curie, CNRS UMR3215, Paris, France.

Abstract

In most mouse tissues, long-interspersed elements-1 (L1s) are silenced via methylation of their 5'-untranslated regions (5'-UTR). A gradual loss-of-methylation in pre-implantation embryos coincides with L1 retrotransposition in blastocysts, generating potentially harmful mutations. Here, we show that Dicer- and Ago2-dependent RNAi restricts L1 accumulation and retrotransposition in undifferentiated mouse embryonic stem cells (mESCs), derived from blastocysts. RNAi correlates with production of Dicer-dependent 22-nt small RNAs mapping to overlapping sense/antisense transcripts produced from the L1 5'-UTR. However, RNA-surveillance pathways simultaneously degrade these transcripts and, consequently, confound the anti-L1 RNAi response. In Dicer(-/-) mESC complementation experiments involving ectopic Dicer expression, L1 silencing was rescued in cells in which microRNAs remained strongly depleted. Furthermore, these cells proliferated and differentiated normally, unlike their non-complemented counterparts. These results shed new light on L1 biology, uncover defensive, in addition to regulatory roles for RNAi, and raise questions on the differentiation defects of Dicer(-/-) mESCs.

PMID:
24244175
PMCID:
PMC3820764
DOI:
10.1371/journal.pgen.1003791
[Indexed for MEDLINE]
Free PMC Article
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