Mitochondrial DNA Haplotypes Define Gene Expression Patterns in Pluripotent and Differentiating Embryonic Stem Cells§

Authors

  • Richard D.W. Kelly,

    1. Mitochondrial Genetics Group, Centre for Reproduction and Development, Monash Institute of Medical ResearchMonash University, Clayton, Victoria, Australia
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  • Andrew E. Rodda,

    1. Mitochondrial Genetics Group, Centre for Reproduction and Development, Monash Institute of Medical ResearchMonash University, Clayton, Victoria, Australia
    2. Department of Materials Engineering, Division of Biological EngineeringMonash University, Clayton, Victoria, Australia
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  • Adam Dickinson,

    1. Mitochondrial Genetics Group, Centre for Reproduction and Development, Monash Institute of Medical ResearchMonash University, Clayton, Victoria, Australia
    2. Warwick Medical School, The University of Warwick, Coventry, United Kingdom
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  • Arsalan Mahmud,

    1. Mitochondrial Genetics Group, Centre for Reproduction and Development, Monash Institute of Medical ResearchMonash University, Clayton, Victoria, Australia
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  • Christian M. Nefzger,

    1. Reprogramming and Epigenetics Laboratory, Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Victoria, Australia
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  • William Lee,

    1. Mitochondrial Genetics Group, Centre for Reproduction and Development, Monash Institute of Medical ResearchMonash University, Clayton, Victoria, Australia
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  • John S. Forsythe,

    1. Department of Materials Engineering, Division of Biological EngineeringMonash University, Clayton, Victoria, Australia
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  • Jose M. Polo,

    1. Reprogramming and Epigenetics Laboratory, Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Victoria, Australia
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  • Ian A. Trounce,

    1. Centre for Eye Research Australia, Department of Ophthalmology, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia
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  • Matthew McKenzie,

    1. Molecular Basis of Mitochondrial Disease Group, Centre for Reproduction and Development, Monash Institute of Medical ResearchMonash University, Clayton, Victoria, Australia
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  • David R. Nisbet,

    1. College of Engineering and Computer Science, Australian National University, Canberra, Australian Capital Territory, Australia
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  • Justin C. St. John

    Corresponding author
    1. Mitochondrial Genetics Group, Centre for Reproduction and Development, Monash Institute of Medical ResearchMonash University, Clayton, Victoria, Australia
    • Monash Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia
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    • Telephone: 61 3 95947401; Fax: 61 3 9594 7416


  • Author contributions: R.D.W.K.: design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; A.E.R.: collection and/or assembly of data and manuscript writing; A.D.: collection and/or assembly of data and data analysis; A.M.: collection of data; C.M.N. and W.L.: collection of data; J.F., J.M.P., I.A.T, and M.McK.: provision of study material and manuscript writing; D.R.N.: conception and design, provision of study material, and manuscript writing; J.C.StJ.: conception and design, financial support, administrative support, data analysis and interpretation, manuscript writing, and final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLS EXPRESS January 10, 2013.

Abstract

Mitochondrial DNA haplotypes are associated with various phenotypes, such as altered susceptibility to disease, environmental adaptations, and aging. Accumulating evidence suggests that mitochondrial DNA is essential for cell differentiation and the cell phenotype. However, the effects of different mitochondrial DNA haplotypes on differentiation and development remain to be determined. Using embryonic stem cell lines possessing the same Mus musculus chromosomes but harboring one of Mus musculus, Mus spretus, or Mus terricolor mitochondrial DNA haplotypes, we have determined the effects of different mitochondrial DNA haplotypes on chromosomal gene expression, differentiation, and mitochondrial metabolism. In undifferentiated and differentiating embryonic stem cells, we observed mitochondrial DNA haplotype-specific expression of genes involved in pluripotency, differentiation, mitochondrial energy metabolism, and DNA methylation. These mitochondrial DNA haplotypes also influenced the potential of embryonic stem cells to produce spontaneously beating cardiomyocytes. The differences in gene expression patterns and cardiomyocyte production were independent of ATP content, oxygen consumption, and respiratory capacity, which until now have been considered to be the primary roles of mitochondrial DNA. Differentiation of embryonic stem cells harboring the different mitochondrial DNA haplotypes in a 3D environment significantly increased chromosomal gene expression for all haplotypes during differentiation. However, haplotype-specific differences in gene expression patterns were maintained in this environment. Taken together, these results provide significant insight into the phenotypic consequences of mitochondrial DNA haplotypes and demonstrate their influence on differentiation and development. We propose that mitochondrial DNA haplotypes play a pivotal role in the process of differentiation and mediate the fate of the cell. STEM CELLS 2013;31:703–716

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