1. Cell Biology
  2. Chromosomes and Gene Expression

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

  1. Qiuying Liu
  2. Xiaoli Chen
  3. Mariah K Novak
  4. Shaojie Zhang
  5. Wenqian Hu  Is a corresponding author
  1. Mayo Clinic, United States
  2. University of Central Florida, United States
https://doi.org/10.7554/eLife.66288
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  1. Qiuying Liu
  2. Xiaoli Chen
  3. Mariah K Novak
  4. Shaojie Zhang
  5. Wenqian Hu
(2021)
Repressing Ago2 mRNA translation by Trim71 maintains pluripotency through inhibiting let-7 microRNAs
eLife 10:e66288.
https://doi.org/10.7554/eLife.66288
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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 is 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.

Data availability

The CLIP-seq, RNA-seq, small-RNA-seq datasets generated during this study are available at GEO: GSE138284

The following data sets were generated

Article and author information

Author details

  1. Qiuying Liu

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Xiaoli Chen

    Department of Computer Science, University of Central Florida, Orlando, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Mariah K Novak

    Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1547-4738

  4. Shaojie Zhang

    Department of Computer Science, University of Central Florida, Orlando, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4051-5549

  5. Wenqian Hu

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    For correspondence
    hu.wenqian@mayo.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3577-3604

Funding

National Heart, Lung, and Blood Institute (R01HL141112)

  • Qiuying Liu
  • Mariah K Novak
  • Wenqian Hu

National Institute of General Medical Sciences (R01GM136869)

  • Qiuying Liu
  • Mariah K Novak
  • Wenqian Hu

National Institute of Allergy and Infectious Diseases (R21AI146431)

  • Xiaoli Chen
  • Shaojie Zhang
  • Wenqian Hu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2021, Liu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Qiuying Liu
  2. Xiaoli Chen
  3. Mariah K Novak
  4. Shaojie Zhang
  5. Wenqian Hu
(2021)
Repressing Ago2 mRNA translation by Trim71 maintains pluripotency through inhibiting let-7 microRNAs
eLife 10:e66288.
https://doi.org/10.7554/eLife.66288

Share this article

https://doi.org/10.7554/eLife.66288

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Further reading

    1. Cell Biology
    2. Chromosomes and Gene Expression

    microRNA-mediated regulation of microRNA machinery controls cell fate decisions

    Qiuying Liu, Mariah K Novak ... Wenqian Hu
    Research Advance Updated

    microRNAs associate with Argonaute proteins, forming the microRNA-induced silencing complex (miRISC), to repress target gene expression post-transcriptionally. Although microRNAs are critical regulators in mammalian cell differentiation, our understanding of how microRNA machinery, such as the miRISC, are regulated during development is still limited. We previously showed that repressing the production of one Argonaute protein, Ago2, by Trim71 is important for mouse embryonic stem cells (mESCs) self-renewal (Liu et al., 2021). Here, we show that among the four Argonaute proteins in mammals, Ago2 is the major developmentally regulated Argonaute protein in mESCs. Moreover, in pluripotency, besides the Trim71-mediated regulation of Ago2 (Liu et al., 2021), Mir182/Mir183 also repress Ago2. Specific inhibition of this microRNA-mediated repression results in stemness defects and accelerated differentiation through the let-7 microRNA pathway. These results reveal a microRNA-mediated regulatory circuit on microRNA machinery that is critical to maintaining pluripotency.