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Updated: Jun 3, 2026
Differentiation of Human Pluripotent Stem Cells Into Pancreatic Beta-Cell Precursors in a 2D Culture System
Published on: December 16, 2021
Dynamic regulation of PDX-1 and FoxO1 expression by FoxA2 in dexamethasone-induced pancreatic β-cells dysfunction
Fang Chen1, Yunxia Zhu, Xinyi Tang
1Key Laboratory of Human Functional Genomics of Jiangsu Province, Clinical Diabetes Centre of Jiangsu Province, Nanjing Medical University, Nanjing 210029, China. hanxiao@njmu.edu.cn
Abstract:
Transcription factors forkhead box (Fox)O1 and pancreatic and duodenal homeobox-1 (PDX-1) are involved in dexamethasone (DEX)-induced dysfunction in pancreatic β-cells. However, the molecular mechanism underlying the regulation of FoxO1 and PDX-1 expression in β-cells treated with DEX is not fully understood. In this study, we found that DEX markedly increased FoxO1 mRNA and protein expression, whereas it decreased PDX-1 mRNA and protein expression in a dose- and time-dependent manner. Further study showed that FoxA2 was involved in regulation of FoxO1 and PDX-1 expression in DEX-induced pancreatic β-cells dysfunction. Interestingly, we demonstrated for the first time that FoxA2 could bind to the FoxO1 gene promoter and positively regulate FoxO1 expression. Moreover, we found that DEX increased the activity of FoxA2 binding to the FoxO1 promoter but decreased the activity of FoxA2 binding to the PDX-1 promoter of RINm5F cells. Knockdown of FoxA2 by RNA interference inhibited FoxO1 expression and restored PDX-1 expression in pancreatic β-cells treated with DEX. However, DEX had no effect on the expression of FoxA2. Together, the results of the present study demonstrated that FoxA2 could dynamically regulate FoxO1 and PDX-1 expression in pancreatic β-cells treated with DEX, which provides new important information on the transcriptional regulation of FoxO1 and PDX-1 in DEX-induced pancreatic β-cells. Inhibition of FoxA2 can effectively protect β-cells against DEX-induced dysfunction.
Insights
Dexamethasone (DEX) disrupts pancreatic beta-cells by altering FoxO1 and PDX-1 expression. The transcription factor FoxA2 dynamically regulates these changes, and inhibiting FoxA2 protects beta-cells from DEX-induced dysfunction.
Area of Science:
- Molecular Biology
- Endocrinology
- Cell Biology
Background:
- Dexamethasone (DEX) induces pancreatic beta-cell dysfunction.
- Transcription factors forkhead box (Fox)O1 and pancreatic and duodenal homeobox-1 (PDX-1) are implicated in this process.
- The precise molecular mechanisms of DEX-induced regulation of FoxO1 and PDX-1 in beta-cells remain unclear.
Purpose of the Study:
- To elucidate the role of FoxA2 in regulating FoxO1 and PDX-1 expression in DEX-treated pancreatic beta-cells.
- To investigate the molecular interactions between FoxA2, FoxO1, and PDX-1 under DEX treatment.
- To determine if targeting FoxA2 can protect beta-cells from DEX-induced dysfunction.
Main Methods:
- Quantitative analysis of FoxO1, PDX-1, and FoxA2 mRNA and protein expression.
- Chromatin immunoprecipitation (ChIP) assays to assess FoxA2 binding to gene promoters.
- RNA interference (RNAi) to knockdown FoxA2 expression.
- Cell viability assays to evaluate beta-cell protection.
Main Results:
- DEX treatment increased FoxO1 expression and decreased PDX-1 expression in a dose- and time-dependent manner.
- FoxA2 directly binds to the FoxO1 promoter, enhancing its expression, and its binding to the PDX-1 promoter is decreased by DEX.
- Knockdown of FoxA2 reversed DEX-induced changes in FoxO1 and PDX-1 expression, protecting beta-cells.
Conclusions:
- FoxA2 plays a critical role in the dynamic regulation of FoxO1 and PDX-1 expression in response to DEX in pancreatic beta-cells.
- Targeting FoxA2 offers a potential therapeutic strategy to protect pancreatic beta-cells from DEX-induced dysfunction.
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