Abstract
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.
Highlights
The switch between pluripotency and differentiation in embryonic stem cells (ESCs) remains incompletely understood
The FLAG-Trim71 mouse embryonic stem cells (mESCs) is phenotypically identical to the wild type (WT) mESC: they have similar morphology, growth rates, self-renewal abilities, and express similar levels of core pluripotency transcription factors (Figure 1—figure supplement 1B–F)
We refer to the FLAG-Trim71 mESCs as the WT mESCs
Summary
The switch between pluripotency and differentiation in embryonic stem cells (ESCs) remains incompletely understood. In terms of biological functions, Trim knockout mice are embryonic lethal (Cuevas et al, 2015), while Trim knockout mouse ESCs (mESCs) have no proliferation or stemness defects (Chang et al, 2012; Mitschka et al, 2015; Welte et al, 2019; Worringer et al, 2014), indicating an enigmatic role of Trim in stem cell biology These results highlight the hypothetical status of Trim71’s function and mechanisms in the bi-stable switch model and beg for investigations on how Trim regulates the let-7 miRNAs and whether this regulation plays a role in controlling pluripotency in stem cells. This study reveals that repressing the conserved pro-differentiation let-7 microRNAs at the mature miRNA level by Ago availability is critical to maintaining pluripotency
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
