Repressing Ago2 mRNA translation by Trim71 maintains pluripotency through inhibiting let-7 microRNAs.
Repressing Ago2 mRNA translation by Trim71 maintains pluripotency through inhibiting let-7 microRNAs.
复制标题
TRIM71抑制AGO2 mRNA翻译通过抑制let-7 microRNA保持多能性。
作者：
Liu Q;Chen X;Novak MK;Zhang S;Hu W
干细胞命运的调控知之甚少。秀丽隐杆线虫的遗传学研究提出了一个假设，即由RNA结合蛋白Trim 71和let-7 microRNA组成的保守的细胞质双负反馈环控制干细胞的多能性和分化。虽然let-7-microRNA介导的Trim 71抑制促进分化，但Trim 71是否以及如何调节多能性并抑制let-7 microRNA仍是未知的。在这里，我们发现Trim 71抑制小鼠胚胎干细胞中Ago 2 mRNA的翻译。阻断这种抑制导致成熟let-7 microRNA的特异性转录后增加，导致let-7依赖性干细胞缺陷和干细胞的加速分化。这些结果不仅支持Trim 71-let-7-microRNA双稳态开关模型在控制干细胞命运中的作用，而且还揭示了通过Ago 2可用性在成熟microRNA水平上抑制保守的促分化let-7 microRNA对于维持多能性至关重要。
The regulation of stem cell fate is poorly understood. Genetic studies in Caenorhabditis elegans lead to the hypothesis that a conserved cytoplasmic double-negative feedback loop consisting of the RNA-binding protein Trim71 and the let-7 microRNA controls the pluripotency and differentiation of stem cells. Although let-7-microRNA-mediated inhibition of Trim71 promotes differentiation, whether and how Trim71 regulates pluripotency and inhibits the let-7 microRNA are still unknown. Here, we show that Trim71 represses Ago2 mRNA translation in mouse embryonic stem cells. Blocking this repression leads to a specific post-transcriptional increase of mature let-7 microRNAs, resulting in let-7-dependent stemness defects and accelerated differentiation in the stem cells. These results not only support the Trim71-let-7-microRNA bi-stable switch model in controlling stem cell fate, but also reveal that repressing the conserved pro-differentiation let-7 microRNAs at the mature microRNA level by Ago2 availability is critical to maintaining pluripotency.