Abstract
Metformin, which is used as a first line treatment for type 2 diabetes mellitus (T2DM), has been shown to affect epigenetic patterns. In this study, we investigated the DNA methylation and potential lncRNA modifications in metformin-treated and newly diagnosed adults with T2DM. Genome-wide DNA methylation and lncRNA analysis were performed from the peripheral blood of 12 screen-detected and 12 metformin-treated T2DM individuals followed by gene ontology (GO) and KEGG pathway analysis. Differentially methylated regions (DMRs) observed showed 22 hypermethylated and 11 hypomethylated DMRs between individuals on metformin compared to screen-detected subjects. Amongst the hypomethylated DMR regions were the SLC gene family, specifically, SLC25A35 and SLC28A1. Fifty-seven lncRNA-associated DNA methylation regions included the mitochondrial ATP synthase-coupling factor 6 (ATP5J). Functional gene mapping and pathway analysis identified regions in the axon initial segment (AIS), node of Ranvier, cell periphery, cleavage furrow, cell surface furrow, and stress fiber. In conclusion, our study has identified a number of DMRs and lncRNA-associated DNA methylation regions in metformin-treated T2DM that are potential targets for therapeutic monitoring in patients with diabetes.
Highlights
DNA methylation, the most widely studied epigenetic mechanism, involves the covalent addition of a methyl group at the 50 position of the cytosine ring within the 50 -CpG-30 dinucleotides to create a 5-methylcytosine (5-mC)
Our findings indicate several novel long non-coding RNAs (lncRNAs), including a lncRNA associated with the mitochondrial ATP synthase-coupling factor 6 (ATP5J) enzyme thought to be involved in the oxidative phosphorylation pathway [35]
Our study has identified a number of differentially methylated regions (DMRs) and lncRNA-associated DNA methylation regions in metformin-treated type 2 diabetes mellitus (T2DM) that are potential targets for therapeutic monitoring in diabetes patients
Summary
DNA methylation, the most widely studied epigenetic mechanism, involves the covalent addition of a methyl group at the 50 position of the cytosine ring within the 50 -CpG-30 dinucleotides to create a 5-methylcytosine (5-mC). Hypermethylation of promoter CpG islands can result in suppression of gene expression, whereas hypomethylation is associated with the transcriptional activation of affected genes [3]. LncRNAs are transcription products greater than 200 nucleotides with limited protein coding function [9] They have been implicated in the regulation gene expression at the epigenetic, transcriptional, and post-transcription level [10]. Metformin was shown to affect DNA methylation even in healthy individuals immediately 10 h after drug administration [19] These alterations in DNA methylation has been evident in cancer related studies, showing that DNA methylation plays a role in the antidiabetic and potential anti-cancer actions of metformin [15,20,21,22]. The knowledge gained could be used as a basis for further studies to elucidate the role of DNA methylation in the monitoring and treatment of T2DM within a South African context
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