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Methodology for Accurate Detection of Mitochondrial DNA Methylation
Published on: May 20, 2018
Experimental mitochondria-targeted DNA methylation identifies GpC methylation, not CpG methylation, as potential
Monique G P van der Wijst1, Amanda Y van Tilburg1, Marcel H J Ruiters1
1Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Hanzeplein 1, 9713, GZ, Groningen, The Netherlands.
Abstract:
Like the nucleus, mitochondria contain their own DNA and recent reports provide accumulating evidence that also the mitochondrial DNA (mtDNA) is subjective to DNA methylation. This evidence includes the demonstration of mitochondria-localised DNA methyltransferases and demethylases, and the detection of mtDNA methylation as well as hydroxymethylation. Importantly, differential mtDNA methylation has been linked to aging and diseases, including cancer and diabetes. However, functionality of mtDNA methylation has not been demonstrated. Therefore, we targeted DNA methylating enzymes (modifying cytosine in the CpG or GpC context) to the mtDNA. Unexpectedly, mtDNA gene expression remained unchanged upon induction of CpG mtDNA methylation, whereas induction of C-methylation in the GpC context decreased mtDNA gene expression. Intriguingly, in the latter case, the three mtDNA promoters were differentially affected in each cell line, while cellular function seemed undisturbed. In conclusion, this is the first study which directly addresses the potential functionality of mtDNA methylation. Giving the important role of mitochondria in health and disease, unravelling the impact of mtDNA methylation adds to our understanding of the role of mitochondria in physiological and pathophysiological processes.
Insights
Mitochondrial DNA (mtDNA) methylation impacts gene expression, with GpC context methylation decreasing it. This study is the first to demonstrate the functionality of mtDNA methylation in cellular processes.
Area of Science:
- Mitochondrial biology
- Epigenetics
- Molecular genetics
Background:
- Mitochondria possess their own DNA (mtDNA), which is increasingly recognized as being subject to DNA methylation.
- Evidence includes the presence of DNA methylating and demethylating enzymes within mitochondria, and detection of methylated and hydroxymethylated mtDNA.
- Differential mtDNA methylation is implicated in aging, cancer, and diabetes, but its functional significance remains unclear.
Purpose of the Study:
- To investigate the functional consequences of DNA methylation within mitochondrial DNA (mtDNA).
- To determine if targeted induction of DNA methylating enzymes in mtDNA affects gene expression and cellular function.
Main Methods:
- Targeted delivery of DNA methylating enzymes to the mitochondria to induce methylation in either CpG or GpC contexts within mtDNA.
- Analysis of mtDNA gene expression levels following induced methylation.
- Assessment of differential effects on mtDNA promoters and overall cellular function.
Main Results:
- Induction of CpG methylation in mtDNA did not alter mtDNA gene expression.
- Induction of GpC methylation in mtDNA led to decreased mtDNA gene expression.
- The three mtDNA promoters were differentially affected by GpC methylation across different cell lines, while overall cellular function remained undisturbed.
Conclusions:
- This study provides the first direct evidence for the functionality of DNA methylation in mtDNA.
- GpC context methylation, but not CpG context methylation, directly impacts mtDNA gene expression.
- Understanding mtDNA methylation's role is crucial for comprehending mitochondrial function in health and disease.
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