The stem cell–specific protein TRIM71 inhibits maturation and activity of the prodifferentiation miRNA let-7 via two independent molecular mechanisms
- Lucia A. Torres-Fernández1,5,
- Sibylle Mitschka1,5,
- Thomas Ulas2,3,4,5,
- Stefan Weise1,
- Kilian Dahm4,
- Matthias Becker2,3,
- Kristian Händler2,3,
- Marc Beyer4,
- Julia Windhausen1,
- Joachim L. Schultze2,3,4 and
- Waldemar Kolanus1
- 1Life and Medical Sciences Institute (LIMES), Molecular Immunology and Cell Biology, University of Bonn, 53115 Bonn, Germany
- 2Systems Medicine, German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany
- 3Platform for Single Cell Genomics and Epigenomics (PRECISE), German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany
- 4Life and Medical Sciences Institute (LIMES), Genomics and Immunoregulation, University of Bonn, 53115 Bonn, Germany
- Corresponding author: torres.fernandez.lucia{at}gmail.com
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↵5 These authors contributed equally to this work.
Abstract
The stem cell–specific RNA-binding protein TRIM71/LIN-41 was the first identified target of the prodifferentiation and tumor suppressor miRNA let-7. TRIM71 has essential functions in embryonic development and a proposed oncogenic role in several cancer types, such as hepatocellular carcinoma. Here, we show that TRIM71 regulates let-7 expression and activity via two independent mechanisms. On the one hand, TRIM71 enhances pre-let-7 degradation through its direct interaction with LIN28 and TUT4, thereby inhibiting let-7 maturation and indirectly promoting the stabilization of let-7 targets. On the other hand, TRIM71 represses the activity of mature let-7 via its RNA-dependent interaction with the RNA-induced silencing complex (RISC) effector protein AGO2. We found that TRIM71 directly binds and stabilizes let-7 targets, suggesting that let-7 activity inhibition occurs on active RISCs. MiRNA enrichment analysis of several transcriptomic data sets from mouse embryonic stem cells and human hepatocellular carcinoma cells suggests that these let-7 regulatory mechanisms shape transcriptomic changes during developmental and oncogenic processes. Altogether, our work reveals a novel role for TRIM71 as a miRNA repressor and sheds light on a dual mechanism of let-7 regulation, uncovering a bistable switch between TRIM71 and let-7 miRNAs that regulates the balance between proliferation and differentiation.
Keywords
- TRIM71/LIN-41
- RNA-binding protein (RBP)
- E3 ubiquitin ligase
- miRNAs
- let-7 family
- AGO2
- LIN28
- TUT4
- embryonic development
- hepatocellular carcinoma
- stem cells and cancer biology
Footnotes
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Article is online at http://www.rnajournal.org/cgi/doi/10.1261/rna.078696.121.
- Received January 29, 2021.
- Accepted April 29, 2021.
- © 2021 Torres-Fernández et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society
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