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Mitochondrial DNA copy number is regulated in a tissue specific manner by DNA methylation of the nuclear-encoded DNA polymerase gamma A

Kelly, Richard D. W., Mahmud, Arsalan, McKenzie, Matthew, Trounce, Ian A. and St John, Justin C. 2012, Mitochondrial DNA copy number is regulated in a tissue specific manner by DNA methylation of the nuclear-encoded DNA polymerase gamma A, Nucleic acids research, vol. 40, no. 20, pp. 10124-10138, doi: 10.1093/nar/gks770.

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Title Mitochondrial DNA copy number is regulated in a tissue specific manner by DNA methylation of the nuclear-encoded DNA polymerase gamma A
Author(s) Kelly, Richard D. W.
Mahmud, Arsalan
McKenzie, MatthewORCID iD for McKenzie, Matthew orcid.org/0000-0001-7508-1800
Trounce, Ian A.
St John, Justin C.
Journal name Nucleic acids research
Volume number 40
Issue number 20
Start page 10124
End page 10138
Total pages 15
Publisher Oxford University Press
Place of publication Oxford, Eng.
Publication date 2012-11-01
ISSN 1362-4962
Keyword(s) Animals
Cell Differentiation
Cell Nucleus
Cells, Cultured
Cellular Reprogramming
DNA Copy Number Variations
DNA Methylation
DNA Polymerase gamma
DNA, Mitochondrial
DNA-Directed DNA Polymerase
Embryonic Stem Cells
Epigenesis, Genetic
Exons
Haplotypes
Mice
Neurogenesis
Pluripotent Stem Cells
RNA Polymerase II
RNA, Messenger
Transcription Elongation, Genetic
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
EMBRYONIC STEM-CELLS
TRANSCRIPTION FACTOR
IN-VITRO
MAMMALIAN DEVELOPMENT
CHROMATIN-STRUCTURE
CPG METHYLATION
CLONED EMBRYOS
GERM-CELLS
REPLICATION
PLURIPOTENT
Summary DNA methylation is an essential mechanism controlling gene expression during differentiation and development. We investigated the epigenetic regulation of the nuclear-encoded, mitochondrial DNA (mtDNA) polymerase γ catalytic subunit (PolgA) by examining the methylation status of a CpG island within exon 2 of PolgA. Bisulphite sequencing identified low methylation levels (<10%) within exon 2 of mouse oocytes, blastocysts and embryonic stem cells (ESCs), while somatic tissues contained significantly higher levels (>40%). In contrast, induced pluripotent stem (iPS) cells and somatic nuclear transfer ESCs were hypermethylated (>20%), indicating abnormal epigenetic reprogramming. Real time PCR analysis of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) immunoprecipitated DNA suggests active DNA methylation and demethylation within exon 2 of PolgA. Moreover, neural differentiation of ESCs promoted de novo methylation and demethylation at the exon 2 locus. Regression analysis demonstrates that cell-specific PolgA expression levels were negatively correlated with DNA methylation within exon 2 and mtDNA copy number. Finally, using chromatin immunoprecipitation (ChIP) against RNA polymerase II (RNApII) phosphorylated on serine 2, we show increased DNA methylation levels are associated with reduced RNApII transcriptional elongation. This is the first study linking nuclear DNA epigenetic regulation with mtDNA regulation during differentiation and cell specialization.
Language eng
DOI 10.1093/nar/gks770
Field of Research 05 Environmental Sciences
06 Biological Sciences
08 Information And Computing Sciences
Copyright notice ©2012, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution non-commercial licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30111622

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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.