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Cell Stem Cell. 2017 Nov 2;21(5):694-703.e7. doi: 10.1016/j.stem.2017.10.004.

An endosiRNA-Based Repression Mechanism Counteracts Transposon Activation during Global DNA Demethylation in Embryonic Stem Cells.

Author information

1
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK; University of Cambridge, The Old Schools, Trinity Lane, Cambridge CB2 1TN, UK. Electronic address: rebecca.berrens@gmail.com.
2
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
3
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK; University of Cambridge, The Old Schools, Trinity Lane, Cambridge CB2 1TN, UK.
4
RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, 230-0045 Kanagawa, Japan.
5
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK. Electronic address: vonmeyenn@babraham.ac.uk.
6
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK; University of Cambridge, The Old Schools, Trinity Lane, Cambridge CB2 1TN, UK; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. Electronic address: wolf.reik@babraham.ac.uk.

Abstract

Erasure of DNA methylation and repressive chromatin marks in the mammalian germline leads to risk of transcriptional activation of transposable elements (TEs). Here, we used mouse embryonic stem cells (ESCs) to identify an endosiRNA-based mechanism involved in suppression of TE transcription. In ESCs with DNA demethylation induced by acute deletion of Dnmt1, we saw an increase in sense transcription at TEs, resulting in an abundance of sense/antisense transcripts leading to high levels of ARGONAUTE2 (AGO2)-bound small RNAs. Inhibition of Dicer or Ago2 expression revealed that small RNAs are involved in an immediate response to demethylation-induced transposon activation, while the deposition of repressive histone marks follows as a chronic response. In vivo, we also found TE-specific endosiRNAs present during primordial germ cell development. Our results suggest that antisense TE transcription is a "trap" that elicits an endosiRNA response to restrain acute transposon activity during epigenetic reprogramming in the mammalian germline.

KEYWORDS:

DNMT1; IAP elements; RNAi; endogenous retroviruses; germ line; primordial germ cell; repeats; small RNAs; transposable element

PMID:
29100015
PMCID:
PMC5678422
DOI:
10.1016/j.stem.2017.10.004
[Indexed for MEDLINE]
Free PMC Article

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