ArticleJournal of diabetes investigation2025
Uhrf1 downregulation promotes β-cell dedifferentiation by decreasing Foxo1 expression in type 2 diabetes.
Article in Journal of diabetes investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Recent advances in pancreatic β-cell dysfunction in type 2 diabetes mellitus: Intracellular stress and dedifferentiation.Journal of diabetes investigation · 2026Article
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4 authors.
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Abstract
backgroundIslet β-cell dedifferentiation is a major pathological mechanism of type 2 diabetes (T2D). Forkhead box o1 (Foxo1) is a master regulator of β-cell dedifferentiation. The mechanisms by which Foxo1 expression is regulated remain unexplored. Epigenetic modification is involved in the occurrence and development of T2D. Ubiquitin-like with PDH and ring finger domains 1 (Uhrf1), as an important epigenetic regulator, is associated with the maintenance of DNA methylation and histone modification. PURPOSE: This study aimed to discover whether Uhrf1 regulates Foxo1 expression and β-cell dedifferentiation of rat insulinoma (INS-1) cells.
methodsRT-qPCR and Western blot were performed to detect the levels of Uhrf1, Foxo1, β-cell dedifferentiation, and proliferation and apoptosis related indicators. ChIP-qPCR was used to analyze the relative lysine trimethylation at positions 4, 9, and 27 on histone H3 (H3K4/9/27me3) enrichment on the Foxo1 promoter. Dual-luciferase reporter assay was performed to assess the interaction between Uhrf1 and Foxo1. Finally, a diabetic rat model was established and the rat islet β-cells were isolated.
resultsGlucolipotoxicity-induced β-cell dedifferentiation of INS-1 cells, which was restored after Uhrf1 overexpression. Mechanistically, Uhrf1 regulated the H3K4/9/27me3 of the Foxo1 promoter region. Besides, Foxo1 overexpression suppressed β-cell dedifferentiation of INS-1 cells. Moreover, islet β-cells isolated from diabetic model rats showed increased dedifferentiation.
conclusionUhrf1 knockdown promoted H3K27me3 and H3K9me3 and reduced H3K4me3 level in INS-1 cells, resulting in the downregulation of Foxo1 expression, thus promoting β-cell dedifferentiation.
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