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The stem cell-specific protein TRIM71 inhibits maturation and activity of the pro-differentiation miRNA let-7 via two independent molecular mechanisms.

ABSTRACT: The stem cell-specific RNA-binding protein TRIM71/LIN-41 was the first identified target of the pro-differentiation 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 datasets 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.

SUBMITTER: Torres Fernandez LA

PROVIDER: S-EPMC8208056 | biostudies-literature |

REPOSITORIES: biostudies-literature

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TRIM71 represses let-7 miRNA expression and activity via two independent molecular mechanisms

Project description:Let-7 is a well-known pro-differentiation and tumor suppressor miRNA. TRIM71/LIN-41 was the first identified let-7 target, and it is a conserved stem cell-specific RNA-binding protein with an essential function in embryonic development and a proposed oncogenic role in several cancer types, such as hepatocellular carcinoma. Previous studies suggest a role for TRIM71 in miRNA regulation, since major changes have been observed in the miRNome of TRIM71-defiecient ESCs, and TRIM71 is able to interact with several proteins involved in the miRNA pathway.

2021-09-09 | GSE163635 | GEO

Different congenital hydrocephalus-associated mutations in Trim71 impair stem cell differentiation via distinct gain-of-function mechanisms.

Project description:Congenital hydrocephalus (CH) is a common neurological disorder affecting many newborns. Imbalanced neurogenesis is a major cause of CH. Multiple CH-associated mutations are within the RNA-binding domain of Trim71, a conserved, stem cell-specific RNA-binding protein. How these mutations alter stem cell fate is unclear. Here, we show that the CH-associated mutations R595H and R783H in Trim71 accelerate differentiation and enhance neural lineage commitment in mouse embryonic stem cells (mESCs), and reduce binding to mRNAs targeted by wild-type Trim71, consistent with previous reports. Unexpectedly, however, each mutant binds an ectopic and distinct repertoire of target mRNAs. R595H-Trim71, but not R783H-Trim71 nor wild-type Trim71, binds the mRNA encoding β-catenin and represses its translation. Increasing β-catenin by overexpression or treatment with a Wnt agonist specifically restores differentiation of R595H-Trim71 mESCs. These results suggest that Trim71 mutations give rise to unique gain-of-function pathological mechanisms in CH. Further, our studies suggest that disruption of the Wnt/β-catenin signaling pathway can be used to stratify disease etiology and develop precision medicine approaches for CH.

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TRIM71 represses let-7 miRNA expression and activity via two independent molecular mechanisms

Project description:TRIM71 represses let-7 miRNA expression and activity via two independent molecular mechanisms

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Sox9-regulated miRNA-574-3p inhibits chondrogenic differentiation of mesenchymal stem cells.

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IFNγ inhibits Th17 differentiation and function via Tbet-dependent and Tbet-independent mechanisms.

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The ubiquitin ligase LIN41/TRIM71 targets p53 to antagonize cell death and differentiation pathways during stem cell differentiation.

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