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

被引：56

作者：

Berrens, Rebecca V. ^{[1
,2
]}

Andrews, Simon ^{[1
]}

Spensberger, Dominik ^{[1
]}

Santos, Fatima ^{[1
,2
]}

Dean, Wendy ^{[1
]}

Gould, Poppy ^{[1
]}

Sharif, Jafar ^{[3
]}

Olova, Nelly ^{[1
,5
]}

Chandra, Tamir ^{[1
,5
]}

Koseki, Haruhiko ^{[3
]}

von Meyenn, Ferdinand ^{[1
]}

Reik, Wolf ^{[1
,2
,4
]}

机构：

[1] Babraham Inst, Epigenet Programme, Cambridge CB22 3AT, England

[2] Univ Cambridge, Old Sch, Trinity Lane, Cambridge CB2 1TN, England

[3] RIKEN, Res Ctr Allergy & Immunol, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan

[4] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England

[5] MRC Inst Genet & Mol Med, MRC Human Genet Unit, Crewe Rd, Edinburgh EH4 2XU, Midlothian, Scotland

来源：

CELL STEM CELL | 2017年 / 21卷 / 05期

基金：

英国惠康基金; 瑞士国家科学基金会; 英国生物技术与生命科学研究理事会;

关键词：

ENDOGENOUS RETROVIRUSES; METHYLATION; RNA; DICER; GERMLINE; EXPRESSION; ELEMENTS; METHYLOME; CHROMATIN; DYNAMICS;

D O I：

10.1016/j.stem.2017.10.004

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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 endo-siRNAs 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.

引用

页码：694 / +

页数：17

共 47 条

[1] A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice [J].