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Uhrf1 downregulation promotes β-cell dedifferentiation by decreasing Foxo1 expression in type 2 diabetes

Lanfang Fu1, Juyun Zhang1, Zhu Lin1

  • 1Department of Endocrinology, Haikou People's Hospital, Haikou, China.

Journal of Diabetes Investigation
|May 23, 2025
PubMed
Abstract

Insights

Ubiquitin-like with PDH and ring finger domains 1 (Uhrf1) epigenetic regulator impacts Forkhead box o1 (Foxo1) expression. Uhrf1 knockdown promotes islet β-cell dedifferentiation in type 2 diabetes by altering Foxo1 promoter methylation.

Area of Science:

  • Endocrinology
  • Epigenetics
  • Molecular Biology

Background:

  • Islet β-cell dedifferentiation is a key mechanism in type 2 diabetes (T2D).
  • Forkhead box o1 (Foxo1) is a critical regulator of β-cell dedifferentiation, but its regulatory mechanisms are unclear.
  • Epigenetic modifications, including DNA methylation and histone modification regulated by Ubiquitin-like with PDH and ring finger domains 1 (Uhrf1), are implicated in T2D pathogenesis.

Purpose of the Study:

  • To investigate whether Uhrf1 regulates Foxo1 expression.
  • To determine if Uhrf1 influences β-cell dedifferentiation in rat insulinoma (INS-1) cells.

Main Methods:

  • Quantitative real-time PCR (RT-qPCR) and Western blotting to assess Uhrf1, Foxo1, and β-cell markers.
  • Chromatin immunoprecipitation followed by qPCR (ChIP-qPCR) to analyze histone trimethylation (H3K4/9/27me3) at the Foxo1 promoter.
  • Dual-luciferase reporter assay to evaluate Uhrf1-Foxo1 interaction.
  • Establishment of a diabetic rat model and isolation of islet β-cells.

Main Results:

  • Uhrf1 overexpression restored glucolipotoxicity-induced β-cell dedifferentiation in INS-1 cells.
  • Uhrf1 was found to regulate H3K4/9/27me3 enrichment on the Foxo1 promoter region.
  • Foxo1 overexpression suppressed β-cell dedifferentiation, and isolated islets from diabetic rats exhibited increased dedifferentiation.

Conclusions:

  • Uhrf1 knockdown in INS-1 cells promoted H3K27me3 and H3K9me3 while reducing H3K4me3 levels.
  • This epigenetic alteration led to the downregulation of Foxo1 expression.
  • The findings indicate that Uhrf1-mediated epigenetic regulation of Foxo1 promotes β-cell dedifferentiation in T2D.
Keywords:
Type 2 diabetesUhrf1β‐cell dedifferentiation

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