Mitochondrial DNA haplotypes induce differential patterns of DNA methylation that result in differential chromosomal gene expression patterns

Mitochondrial DNA copy number is strictly regulated during development as naive cells differentiate into mature cells to ensure that specific cell types have sufficient copies of mitochondrial DNA to perform their specialised functions. Mitochondrial DNA haplotypes are defined as specific regions of...

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Published inCell death discovery Vol. 3; no. 1; p. 17062
Main Authors Lee, William T, Sun, Xin, Tsai, Te-Sha, Johnson, Jacqueline L, Gould, Jodee A, Garama, Daniel J, Gough, Daniel J, McKenzie, Matthew, Trounce, Ian A, St. John, Justin C
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.01.2017
Springer Nature B.V
Nature Publishing Group
Subjects
Apoptosis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Cycle Analysis
Cell lines
Chromosomes
Copy number
Demethylation
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA methylation
Gene expression
Haplotypes
Ketoglutaric acid
Life Sciences
Mitochondrial DNA
Nucleotide sequence
Phylogeny
Stem Cells
Tricarboxylic acid cycle
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Summary:Mitochondrial DNA copy number is strictly regulated during development as naive cells differentiate into mature cells to ensure that specific cell types have sufficient copies of mitochondrial DNA to perform their specialised functions. Mitochondrial DNA haplotypes are defined as specific regions of mitochondrial DNA that cluster with other mitochondrial sequences to show the phylogenetic origins of maternal lineages. Mitochondrial DNA haplotypes are associated with a range of phenotypes and disease. To understand how mitochondrial DNA haplotypes induce these characteristics, we used four embryonic stem cell lines that have the same set of chromosomes but possess different mitochondrial DNA haplotypes. We show that mitochondrial DNA haplotypes influence changes in chromosomal gene expression and affinity for nuclear-encoded mitochondrial DNA replication factors to modulate mitochondrial DNA copy number, two events that act synchronously during differentiation. Global DNA methylation analysis showed that each haplotype induces distinct DNA methylation patterns, which, when modulated by DNA demethylation agents, resulted in skewed gene expression patterns that highlight the effectiveness of the new DNA methylation patterns established by each haplotype. The haplotypes differentially regulate α -ketoglutarate, a metabolite from the TCA cycle that modulates the TET family of proteins, which catalyse the transition from 5-methylcytosine, indicative of DNA methylation, to 5-hydroxymethylcytosine, indicative of DNA demethylation. Our outcomes show that mitochondrial DNA haplotypes differentially modulate chromosomal gene expression patterns of naive and differentiating cells by establishing mitochondrial DNA haplotype-specific DNA methylation patterns.
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These authors all contributed equally to this work.
WTL, XS, T-ST and JCSJ designed the study. WTL, XS, T-ST, JLJ, JAG, DJG, DJG and MM performed the experiments. WTL, XS, T-ST, JAG, DJG, DJG, MM, IAT and JCSJ analysed the data. WTL, XS, T-ST, JAG, DJG, DJG, MM, IAT and JCSJ wrote and edited the manuscript.
ISSN:2058-7716
2058-7716
DOI:10.1038/cddiscovery.2017.62