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

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, w...

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Bibliographic Details
Published in:PLoS genetics 2013-11, Vol.9 (11), p.e1003791-e1003791
Main Authors: Ciaudo, Constance, Jay, Florence, Okamoto, Ikuhiro, Chen, Chong-Jian, Sarazin, Alexis, Servant, Nicolas, Barillot, Emmanuel, Heard, Edith, Voinnet, Olivier
Format: Article
Language:English
Subjects:
5' Untranslated Regions
Animals
Argonaute Proteins - genetics
Cell Differentiation - genetics
Cell Proliferation
DEAD-box RNA Helicases - genetics
DEAD-box RNA Helicases - metabolism
DNA Methylation - genetics
Embryonic Stem Cells - metabolism
Experiments
Gene Expression Regulation, Developmental
Genetic aspects
Genomes
Long Interspersed Nucleotide Elements - genetics
Mammals
Mice
MicroRNAs
Physiological aspects
Promoter Regions, Genetic
Proteins
Retroelements - genetics
Ribonuclease III - genetics
Ribonuclease III - metabolism
RNA Interference
RNA sequencing
Stem cells
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1003791