Repressing ago2 mrna translation by trim71 maintains pluripotency through inhibiting let-7 micrornas

Qiuying Liu; Xiaoli Chen; Mariah K. Novak; Shaojie Zhang; Wenqian Hu

doi:10.7554/eLife.66288

Repressing ago2 mrna translation by trim71 maintains pluripotency through inhibiting let-7 micrornas

Qiuying Liu, Xiaoli Chen, Mariah K. Novak, Shaojie Zhang, Wenqian Hu

Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English (US)
Article number	e66288
Pages (from-to)	1-27
Number of pages	27
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/eLife.66288
State	Published - Feb 2021

ASJC Scopus subject areas

Neuroscience(all)
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)

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10.7554/eLife.66288

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title = "Repressing ago2 mrna translation by trim71 maintains pluripotency through inhibiting let-7 micrornas",

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.",

author = "Qiuying Liu and Xiaoli Chen and Novak, {Mariah K.} and Shaojie Zhang and Wenqian Hu",

note = "Funding Information: We thank Drs. Juan R Alvarez-Dominguez and Lei Sun for critical comments, and Dr. Jianfu Chen for the FLAG-Trim71 plasmid. This work was supported by NIH grants (R01HL141112, R01GM136869, and R21AI146431) and Mayo Foundation for Medical Education and Research. Funding Information: National Heart, Lung, and Blood Institute R01HL141112 National Institute of General Medical Sciences R01GM136869 National Institute of Allergy and Infectious Diseases R21AI146431. Publisher Copyright: {\textcopyright} Liu et al.",

year = "2021",

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AU - Hu, Wenqian

N1 - Funding Information: We thank Drs. Juan R Alvarez-Dominguez and Lei Sun for critical comments, and Dr. Jianfu Chen for the FLAG-Trim71 plasmid. This work was supported by NIH grants (R01HL141112, R01GM136869, and R21AI146431) and Mayo Foundation for Medical Education and Research. Funding Information: National Heart, Lung, and Blood Institute R01HL141112 National Institute of General Medical Sciences R01GM136869 National Institute of Allergy and Infectious Diseases R21AI146431. Publisher Copyright: © Liu et al.

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N2 - 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.

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Repressing ago2 mrna translation by trim71 maintains pluripotency through inhibiting let-7 micrornas

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