Figure 1.

DNA methylation and mtDNA replication. Primordial germ cells, the very first germ cells laid down, possess very few copies of mtDNA. During oogenesis, mtDNA copy number increases exponentially to cross the threshold (broken blue line) that is required for the mature, metaphase II oocyte to complete fertilisation and preimplantation development. Throughout preimplantation development, mtDNA copy number decreases and mtDNA replication is then initiated at the blastocyst stage, but this is restricted to the trophectodermal cells. On the other hand, the cells of the inner cell mass continue to reduce mtDNA copy number. As a result, the developing embryo establishes the mtDNA set point, the founder molecules of mtDNA that contribute to the cells, tissues and organs of the foetus and offspring, which takes place before differentiation. Once naïve cells commit to a specific lineage, mtDNA replication takes place in a cell-specific manner, which allows cells to perform their specialized functions by allowing them to utilise oxidative phosphorylation (OXPHOS), if required. To this extent, cells (heart, muscle, neurons) that primarily have a high requirement for ATP through OXPHOS will have high mtDNA copy number and those with a low requirement for OXPHOS (blood) will tend to have lower mtDNA copy number and predominantly utilise glycolysis. Throughout development, there are synchronous changes to DNA methylation and gene expression. Translocation methylcytosine dioxygenases (TET) enzymes are responsible for erasing parental DNA methylation patterns through to the blastocyst stage. However, the de novo methyltransferases, for example DNMT3a and DNMT3b mediate de novo DNA methylation through preimplantation development and onwards. DNMT1 is then employed to maintain cell-specific DNA methylation profiles.