Differential DNA Methylation and Expression of MicroRNAs in Adipose Tissue from Twin Pairs Discordant for Type 2 Diabetes
semanticscholar(2021)
摘要
The prevalence of type 2 diabetes (T2D) is increasing worldwide but
current treatments have limitations. MicroRNAs (miRNAs) may play a key
role in the development of T2D and can be targets for novel therapies.
Here, we examined whether T2D is associated with altered expression and
DNA-methylation of miRNAs using adipose tissue from 14 monozygotic twin
pairs discordant for T2D. Four members each of the miR-30 and
let-7-families were downregulated in adipose tissue from subjects with
T2D, which was confirmed in an independent case-control cohort. Further,
DNA-methylation of five CpG sites annotated to gene promoters of
differentially expressed miRNAs, including miR-30a and let-7a-3, was
increased in T2D subjects. Luciferase experiments showed that increased
DNA methylation of the miR-30a promoter reduced its transcription.
Silencing of miR-30 in adipocytes resulted in reduced glucose uptake and
TBC1D4 phosphorylation; downregulation of genes involved in
demethylation and carbohydrate/lipid/amino acid metabolism; and
upregulation of inflammatory genes. In conclusion, T2D is associated
with differential DNA methylation and expression of miRNAs in adipose
tissue. Downregulation of the miR-30 and let-7-families may lead to
reduced glucose uptake and altered expression of key genes associated
with T2D.
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