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TCF7L2 regulates pancreatic β-cell function through PI3K/AKT signal pathway
Hui-Hui Wu1, Yan-Liang Li2, Nai-Jia Liu2
1Department of Endocrinology and Metabolism, Jing'an District Center Hospital of Shanghai, Shanghai, 200040 China.
Background:
Transcription factor 7-like 2 (TCF7L2), which previously known as TCF-4, is a major form of transcription factor involved in the downstream WNT signaling and exhibits the strongest association to diabetes susceptibility. Although we still do not know mechanistically how TCF7L2 exerts its physiological functions on pancreatic endocrine cells, it had been suggested that TCF7L2 may directly affect β-cell function by regulating the activation of PI3K/AKT signaling pathway.
Methods:
MIN6 cells were transfected with TCF7L2 knockdown virus or lenti-TCF7L2 virus for 48 h to evaluate the contribution of TCF7L2 to the PI3K/AKT signaling pathway and pancreatic β-cell function. This was confirmed by measuring the expression of PI3K p85 and p-Akt by western blotting and insulin secretion by enzyme-linked immunosorbent assay (ELISA), respectively. Chromatin immunoprecipitation (ChIP) and polymerase chain reaction (PCR) experiments were performed to explore the genomic distribution of TCF7L2-binding sites in the promoter of PIK3R1, the affinity between which was analyzed by the luciferase reporter assay.
Results:
In the present study, we strikingly identified that TCF7L2 could profoundly inhibit the expression of PIK3R1 gene and its encoding protein PI3K p85, which then could lead to the activation of PI3K/AKT signaling and stimulate insulin secretion in pancreatic β-cells. However, the integrity and stability of evolutionarily conserved TCF7L2-binding motif plays a very crucial role in the binding events between transcription factor TCF7L2 and its candidate target genes. We also found that the affinity of TCF7L2 to the promoter region of PIK3R1 alters upon the specific binding sites, which further provides statistical validation to the necessity of TCF7L2-binding motif.
Conclusions:
This study demonstrated that TCF7L2 is closely bound to the specific binding regions of PIK3R1 promoter and prominently controls the transcription of its encoding protein p85, which further affects the activation of PI3K/AKT signaling pathway and insulin secretion.
Insights
Transcription factor 7-like 2 (TCF7L2) inhibits PIK3R1 gene expression, impacting the PI3K/AKT pathway and insulin secretion in pancreatic beta cells. This finding is crucial for understanding diabetes susceptibility.
Area of Science:
- Molecular Biology
- Endocrinology
- Genetics
Background:
- Transcription factor 7-like 2 (TCF7L2) is linked to diabetes susceptibility and influences WNT signaling.
- TCF7L2's role in pancreatic beta-cell function, particularly its regulation of the PI3K/AKT pathway, is not fully understood.
Purpose of the Study:
- To investigate the mechanistic role of TCF7L2 in regulating pancreatic beta-cell function.
- To elucidate the relationship between TCF7L2, PI3K/AKT signaling, and insulin secretion.
Main Methods:
- MIN6 cells were manipulated using TCF7L2 knockdown or overexpression viruses.
- Western blotting assessed PI3K p85 and p-Akt expression; ELISA measured insulin secretion.
- Chromatin immunoprecipitation, PCR, and luciferase reporter assays identified TCF7L2 binding sites in the PIK3R1 promoter.
Main Results:
- TCF7L2 significantly inhibited PIK3R1 gene and PI3K p85 protein expression.
- This inhibition led to PI3K/AKT pathway activation and stimulated insulin secretion.
- The TCF7L2-binding motif's integrity was critical for binding affinity to the PIK3R1 promoter.
Conclusions:
- TCF7L2 binds to specific regions of the PIK3R1 promoter, controlling p85 transcription.
- TCF7L2 influences PI3K/AKT signaling activation and insulin secretion in pancreatic beta cells.
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