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Original article
No correlation between mtDNA amount and methylation levels at the CpG island of POLG exon 2 in wild-type and mutant human differentiated cells
  1. Julie Steffann1,
  2. Aurore Pouliet1,
  3. Houda Adjal1,
  4. Christine Bole1,
  5. Cécile Fourrage1,
  6. Jelena Martinovic2,
  7. Louise Rolland-Galmiche1,
  8. Agnes Rotig1,
  9. Frédéric Tores1,
  10. Arnold Munnich1,
  11. Jean-Paul Bonnefont1
  1. 1Imagine Institute UMR1163, and Paris Descartes University, Hôpital Necker-Enfants Malades, Paris Cedex, France
  2. 2Fœtopathologie, Hôpital Antoine-Béclère, Clamart, France
  1. Correspondence to Professor Julie Steffann, Imagine Institute UMR1163, and Paris Descartes University, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France; julie.steffann{at}


Background While mitochondrial DNA (mtDNA) copy number is strictly regulated during differentiation and according to cell type, very little is known regarding the mechanism which accurately controls mtDNA copy number in human. Exon 2 of the human POLG gene, encoding the catalytic subunit of the mitochondrial-specific DNA polymerase gamma, contains a CpG island, highly conserved in mice and human. Changes of DNA methylation at the POLG locus have been shown to modulate mtDNA copy number during cell differentiation in both mouse and human.

Methods We have investigated the epigenetic modification of the POLG gene, by assessing the methylation level of its exon 2 using deep-Next Generation Sequencing analysis of bisulfite-treated DNA. Analysis were performed on various tissues at either postnatal or prenatal stages, on samples from carriers of mtDNA mutations, patients carrying two loss-of-function POLG mutations and controls.

Results Very high methylation levels at POLG exon 2 were found (94±3%) and no variation was observed according to either developmental stage or tissue of origin, except for sperm samples for which lower methylation levels were found (80%). This high level of methylation was neither correlated with the presence of mtDNA mutations (94±1% of methylated alleles), nor with biallelic POLG mutations (93%±2%), even in tissues where a mtDNA depletion had been observed.

Conclusions This study suggests that, at variance with mouse and un/de-differentiated human cells, differentiated human cells control mtDNA levels irrespective of POLG methylation. The factors which actually control the mtDNA levels in such cell types remain to be identified.

  • methylation
  • POLG
  • mitochondrial DNA
  • mitochondria
  • mutation

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  • Contributors JS and J-PB planned and supervised the study. AP and HA performed the experiments. CB, LR-G, JM and AR contributed to reagents, materials and analysis tools. Bioinformatic data analysis was performed by CF and FT. JS and J-PB analysed the data. JS, JP-B and AM wrote the manuscript.

  • Funding This work was supported by “Agence de la Biomedecine”.

  • Competing interests None declared.

  • Ethics approval Agence de la Biomedecine.

  • Provenance and peer review Not commissioned; externally peer reviewed.