Regulation of mammalian totipotency: a molecular perspective from in vivo and in vitro studies

In mammals, cells acquire totipotency at fertilization. Embryonic genome activation (EGA), which occurs at the 2-cell stage in the mouse and 4- to 8-cell stage in humans, occurs during the time window at which embryonic cells are totipotent and thus it is thought that EGA is mechanistically linked to the foundations of totipotency. The molecular mechanisms that lead to the establishment of totipotency and EGA had been elusive for a long time, however, recent advances have been achieved with the establishment of new cell lines with greater developmental potential and the application of novel low-input high-throughput techniques in embryos. These have unveiled several principles of totipotency related to its epigenetic makeup but also to characteristic features of totipotent cells. In this review, we summarize and discuss current views exploring some of the key drivers of totipotency from both in vitro cell culture models and embryogenesis in vivo.