Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK; University of Cambridge, The Old Schools, Trinity Lane, Cambridge CB2 1TN, UK.
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
Cell Stem Cell. 2017 Nov 2;21(5):694-703.e7. doi: 10.1016/j.stem.2017.10.004.
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.
哺乳动物生殖系中 DNA 甲基化和抑制性染色质标记的消除会导致转座元件 (TEs) 的转录激活风险。在这里，我们使用小鼠胚胎干细胞 (ESCs) 来鉴定一种涉及 TE 转录抑制的内源性 siRNA 机制。在急性缺失 Dnmt1 导致 DNA 去甲基化的 ESCs 中，我们观察到 TE 上的 sense 转录增加，导致 sense/antisense 转录本丰富，从而导致高水平的 ARGONAUTE2 (AGO2) 结合小 RNA。抑制 Dicer 或 Ago2 的表达表明小 RNA 参与了对去甲基化诱导的转座子激活的即时反应，而抑制性组蛋白标记的沉积则是慢性反应。在体内，我们还发现了在原始生殖细胞发育过程中存在的特定于 TE 的内源性 siRNA。我们的研究结果表明，反义 TE 转录是一种“陷阱”，它引发内源性 siRNA 反应，以限制哺乳动物生殖系中表观遗传重编程期间急性转座子活性。
