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.
Publication types
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Research Support, Non-U.S. Gov't
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Retracted Publication
MeSH terms
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5' Untranslated Regions
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Animals
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Argonaute Proteins / genetics*
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Cell Differentiation / genetics
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Cell Proliferation
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DEAD-box RNA Helicases / genetics*
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DEAD-box RNA Helicases / metabolism
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DNA Methylation / genetics
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Embryonic Stem Cells / metabolism*
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Gene Expression Regulation, Developmental
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Long Interspersed Nucleotide Elements / genetics*
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Mice
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Promoter Regions, Genetic
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RNA Interference*
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Retroelements / genetics
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Ribonuclease III / genetics*
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Ribonuclease III / metabolism
Substances
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5' Untranslated Regions
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Ago2 protein, mouse
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Argonaute Proteins
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Retroelements
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Dicer1 protein, mouse
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Ribonuclease III
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DEAD-box RNA Helicases
Grants and funding
This work was supported by the ANR grant “RNA ES”; to both EH and OV. OV's laboratory was further supported by an ERC Young Investigator Award (Grant ERC-210890 “Frontiers of RNAi”) and Prix Liliane Bettencourt for Life Sciences. EH is a member of the European Network of excellence “Epigenesis”. CC was supported by a post-doctoral fellowship from the Federation of European Biochemical Societies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.