Abstract
SummaryErasure 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.
Highlights
Epigenetic reprogramming in the mammalian germline is key for restoration of developmental potency and occurs at the preimplantation stage of embryonic development and during development of primordial germ cells (PGCs) (Reik and Surani, 2015)
Acute Dnmt1 Deletion Leads to transposable elements (TEs) Demethylation in embryonic stem cells (ESCs) Our experimental system recapitulates epigenetic reprogramming of early embryos and PGCs in vitro
By whole-genome bisulfite sequencing (WGBS-seq), we confirmed that acute deletion of Dnmt1 led to genome-wide demethylation from an initial 85% CpG methylation to 35% at day 3 after deletion, and 20% at day 6 after deletion with no further demethylation thereafter (Figures 1B and S1A)
Summary
Epigenetic reprogramming in the mammalian germline is key for restoration of developmental potency and occurs at the preimplantation stage of embryonic development and during development of primordial germ cells (PGCs) (Reik and Surani, 2015). These events lead to global DNA methylation and H3K9me erasure together with the transient transcriptional activation of specific classes of transposable elements (TEs) (Hajkova et al, 2008; Rowe and Trono, 2011). The ERV family members intracisternal A particles (IAPs) and early transposons (ETns) are the most active TEs in the murine germline (Maksakova et al, 2006)
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