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dc.contributor.authorLee, WT
dc.contributor.authorSun, X
dc.contributor.authorTsai, T-S
dc.contributor.authorJohnson, JL
dc.contributor.authorGould, JA
dc.contributor.authorGarama, DJ
dc.contributor.authorGough, DJ
dc.contributor.authorMcKenzie, M
dc.contributor.authorTrounce, IA
dc.contributor.authorSt John, JC
dc.date.accessioned2020-12-21T02:28:15Z
dc.date.available2020-12-21T02:28:15Z
dc.date.issued2017-01-01
dc.identifier.citationLee, W. T., Sun, X., Tsai, T. -S., Johnson, J. L., Gould, J. A., Garama, D. J., Gough, D. J., McKenzie, M., Trounce, I. A. & St John, J. C. (2017). Mitochondrial DNA haplotypes induce differential patterns of DNA methylation that result in differential chromosomal gene expression patterns. CELL DEATH DISCOVERY, 3 (1), https://doi.org/10.1038/cddiscovery.2017.62.
dc.identifier.issn2058-7716
dc.identifier.urihttp://hdl.handle.net/11343/256940
dc.description.abstractMitochondrial 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.
dc.languageEnglish
dc.publisherNATURE PUBLISHING GROUP
dc.titleMitochondrial DNA haplotypes induce differential patterns of DNA methylation that result in differential chromosomal gene expression patterns
dc.typeJournal Article
dc.identifier.doi10.1038/cddiscovery.2017.62
melbourne.affiliation.departmentMelbourne Medical School
melbourne.source.titleCell Death Discovery
melbourne.source.volume3
melbourne.source.issue1
dc.rights.licenseCC BY
melbourne.elementsid1235328
melbourne.contributor.authorTrounce, Ian
dc.identifier.eissn2058-7716
melbourne.accessrightsOpen Access


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