Repressing Ago2 mRNA translation by Trim71 maintains pluripotency through inhibiting let-7 microRNAs

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 prodifferentiation let-7 microRNAs at the mature microRNA level by Ago2 availability is critical to maintaining pluripotency.

Automated summary

Research shows that Trim71 represses Ago2 mRNA translation in mouse embryonic stem cells, which leads to an increase in mature let-7 microRNAs and affects stemness and differentiation. This highlights the importance of repressing the prodifferentiation let-7 microRNAs for maintaining pluripotency.