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

Lee, William T., Sun, Xin, Tsai, Te-Sha, Johnson, Jacqueline L., Gould, Jodee A., Garama, Daniel J., Gough, Danel J., McKenzie, Matthew, Trounce, Ian A. and St John, Justin C. 2017, Mitochondrial DNA haplotypes induce differential patterns of DNA methylation that result in differential chromosomal gene expression patterns, Cell Death Discovery, vol. 3, pp. 1-11, doi: 10.1038/cddiscovery.2017.62.

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Title Mitochondrial DNA haplotypes induce differential patterns of DNA methylation that result in differential chromosomal gene expression patterns
Author(s) Lee, William T.
Sun, Xin
Tsai, Te-Sha
Johnson, Jacqueline L.
Gould, Jodee A.
Garama, Daniel J.
Gough, Danel J.
McKenzie, MatthewORCID iD for McKenzie, Matthew orcid.org/0000-0001-7508-1800
Trounce, Ian A.
St John, Justin C.
Journal name Cell Death Discovery
Volume number 3
Article ID 17062
Start page 1
End page 11
Total pages 11
Publisher Nature Publishing Group
Place of publication London, Eng.
Publication date 2017
ISSN 2058-7716
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.
Language eng
DOI 10.1038/cddiscovery.2017.62
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2017, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30111621

Document type: Journal Article
Collections: School of Life and Environmental Sciences
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.