DNA methylation status of nuclear-encoded mitochondrial genes underlies the tissue-dependent mitochondrial functions.
BACKGROUND
Mitochondria are semi-autonomous, semi-self-replicating organelles harboring their own DNA (mitochondrial DNA, mtDNA), and their dysregulation is involved in the development of various diseases. While mtDNA does not generally undergo epigenetic modifications, almost all mitochondrial proteins are encoded by nuclear DNA. However, the epigenetic regulation of nuclear-encoded mitochondrial genes (nuclear mt genes) has not been comprehensively analyzed.


RESULTS
We analyzed the DNA methylation status of 899 nuclear mt genes in the liver, brain, and heart tissues of mouse, and identified 636 nuclear mt genes carrying tissue-dependent and differentially methylated regions (T-DMRs). These nuclear mt genes are involved in various mitochondrial functions and they also include genes related to human diseases. T-DMRs regulate the expression of nuclear mt genes. Nuclear mt genes with tissue-specific hypomethylated T-DMRs were characterized by enrichment of the target genes of specific transcription factors such as FOXA2 in the liver, and CEBPA and STAT1 in the brain.


CONCLUSIONS
A substantial proportion of nuclear mt genes contained T-DMRs, and the DNA methylation status of numerous T-DMRs should underlie tissue-dependent mitochondrial functions.
Takasugi
Masaki
M
Laboratory of Cellular Biochemistry, Department of Animal Resource Science/Veterinary Medical Sciences, the University of Tolyo, Tokyo 113-8657, Japan.
Yagi
Shintaro
S
Hirabayashi
Keiji
K
Shiota
Kunio
K
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D005786:Gene Expression Regulation; D050259:Genes, Mitochondrial / Q000235:genetics*; D016678:Genome / Q000235:genetics; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D008957:Models, Genetic; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D015183:Restriction Mapping; D024363:Transcription Initiation Site
C496503:Foxa2 protein, mouse; D051542:Hepatocyte Nuclear Factor 3-beta