MicroRNA-34a and promoter methylation contribute to peroxisome proliferator-activated receptor gamma gene expression in patients with type 2 diabetes

• Published in: Diabetes & metabolic syndrome clinical research & reviews Vol. 18; no. 10; p. 103156
• Main Authors: Moghadasi, Mona, Taherimoghaddam, Mozhgan, Babaeenezhad, Esmaeel, Birjandi, Mehdi, Kaviani, Mozhgan, Moradi Sarabi, Mostafa
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01-10-2024
• Subjects: DNA methylation; Gene expression; miR-34a; PPARγ; Type 2 diabetes; Type 2 diabetes; DNA methylation; Gene expression; miR-34a; PPARγ
• ISSN: 1871-4021; 1878-0334; 1878-0334
• DOI: 10.1016/j.dsx.2024.103156

This study aimed to investigate the roles of DNA methylation and miR-34a in the regulation of peroxisome proliferator-activated receptor gamma (PPARγ) in patients with type 2 diabetes (T2D).
We investigated the methylation status of four regions of the PPARγ promoter and PPARγ expression in a panel of 84 T2D patients using methylation-specific PCR (MSP) and RT-qPCR, respectively. Moreover, we quantified DNA methyltransferases (DNMTs) expression and global DNA methylation levels by RT-qPCR and ELISA, respectively. We measured the expression levels of miR-34a and protein expression of PPARγ by stem-loop RT-qPCR and ELISA, respectively.
We found significant DNA hypermethylation in the R2 and R3 regions of the PPARγ promoter in people with diabetes. Functionally, this was associated with a significant reduction in PPARγ expression. In addition, we observed a significant increase in 5-methylcytosine levels in people with diabetes. A marked increase in circulating miR-34a in the early stages of T2D (up to 10 years) and a significant decrease in circulating miR-34a with increasing diabetes duration from 10 years after the onset of diabetes. Interestingly, upregulation of DNA methyltransferases 1 (DNMT1), DNMT3A, and DNMT3B was observed in people with diabetes, and the average expression of DNMTs was negatively correlated with circulating miR-34a levels. In contrast, the serum protein level of PPARγ, a direct target of miR-34a, increased considerably with diabetes duration and showed a negative correlation with circulating miR-34a, cholesterol, triglyceride, and low-density lipoprotein.
PPARγ promoter hypermethylation and miR-34a upregulation are associated with T2D pathogenesis through PPARγ dysregulation.
•We investigated the effects of promoter methylation and microRNA-34a on peroxisome proliferator-activated receptor gamma expression in people with type 2 diabetes.•The expression level of microRNA-34a increased up to the first ten years of diabetes, but decreased with diabetes progression.•We found epigenetic silencing of peroxisome proliferator-activated receptor gamma and an inverse correlation between its protein levels and microRNA-34a.