Regional differences in mitochondrial DNA methylation in human post-mortem brain tissueReport as inadecuate

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Clinical Epigenetics

, 9:47

Neurology and psychiatry


BackgroundDNA methylation is an important epigenetic mechanism involved in gene regulation, with alterations in DNA methylation in the nuclear genome being linked to numerous complex diseases. Mitochondrial DNA methylation is a phenomenon that is receiving ever-increasing interest, particularly in diseases characterized by mitochondrial dysfunction; however, most studies have been limited to the investigation of specific target regions. Analyses spanning the entire mitochondrial genome have been limited, potentially due to the amount of input DNA required. Further, mitochondrial genetic studies have been previously confounded by nuclear-mitochondrial pseudogenes. Methylated DNA Immunoprecipitation Sequencing is a technique widely used to profile DNA methylation across the nuclear genome; however, reads mapped to mitochondrial DNA are often discarded. Here, we have developed an approach to control for nuclear-mitochondrial pseudogenes within Methylated DNA Immunoprecipitation Sequencing data. We highlight the utility of this approach in identifying differences in mitochondrial DNA methylation across regions of the human brain and pre-mortem blood.

ResultsWe were able to correlate mitochondrial DNA methylation patterns between the cortex, cerebellum and blood. We identified 74 nominally significant differentially methylated regions p < 0.05 in the mitochondrial genome, between anatomically separate cortical regions and the cerebellum in matched samples N = 3 matched donors. Further analysis identified eight significant differentially methylated regions between the total cortex and cerebellum after correcting for multiple testing. Using unsupervised hierarchical clustering analysis of the mitochondrial DNA methylome, we were able to identify tissue-specific patterns of mitochondrial DNA methylation between blood, cerebellum and cortex.

ConclusionsOur study represents a comprehensive analysis of the mitochondrial methylome using pre-existing Methylated DNA Immunoprecipitation Sequencing data to identify brain region-specific patterns of mitochondrial DNA methylation.

Keywords5-mC 5-Methylcytosine Blood Brain DNA methylation Epigenetics MeDIP-seq Mitochondria NUMTs Abbreviations5-mC5-methylcytosine

BABrodmann area

DMRDifferentially methylated region

MeDIP-seqMethylated DNA Immunoprecipitation Sequencing

mtDNAMitochondrial DNA

ncDNANuclear DNA

NUMTsNuclear-mitochondrial DNA

PCAPrincipal component analysis

rRNARibosomal ribonucleic acid

tRNATransfer ribonucleic acid

Author: Matthew Devall - Rebecca G. Smith - Aaron Jeffries - Eilis Hannon - Matthew N. Davies - Leonard Schalkwyk - Jonathan Mill



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