TGF-β1 alters DNA methylation levels in promoter and enhancer regions of the WT1 gene in human podocytes

Nephrology
Hiroko HamataniKeiju Hiromura

Abstract

Wilms' tumour 1 (WT1) is essential for normal podocyte function. Previous reports have demonstrated that the WT1 promoter is often methylated in cancers, leading to transcriptional silencing. Transforming growth factor-β1 (TGF-β1) is reported to down-regulate WT1 expression in podocytes. Based on the hypothesis that epigenetic modification plays a role in this process, we examined whether TGF-β1 affects the methylation status of WT1 regulatory regions. Conditional immortalized human podocytes were treated with TGF-β1. A human renal proximal tubular epithelial cell line (HK2), which does not express WT1, was used as a control. The degree of DNA methylation of the WT1 promoter, 5' enhancer, intron 3 enhancer and 3' enhancer was determined using quantitative methylation-specific PCR, bisulfite sequencing and pyrosequencing. Both WT1 mRNA and protein expression were reduced by long-term treatment with TGF-β1. The WT1 promoter was hypomethylated, and the 5' enhancer and intron 3 enhancer were substantially methylated in untreated podocytes. In contrast, in HK2 cells, the WT1 promoter was strongly methylated, and the 5' enhancer and intron 3 enhancer were less methylated than in untreated podocytes. TGF-β1 tended to increase WT1 prom...Continue Reading

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