Exit from totipotency in mammals: an epigenetic perspective

Totipotency is the ability of a single cell to generate a whole organism and is a property restricted to the cells of the earliest embryonic developmental stages. Interestingly, the process of zygotic genome activation (ZGA), which mediates in the embryo the switch from maternal inherited RNAs to embryonic transcripts, has been associated with the loss of totipotency potential. The exit from totipotency correlates with the quick and efficient silencing of a totipotent-associated stage-specific transcriptional program triggered during ZGA. Importantly, the timely and efficient silencing is required for proper embryonic development. However, the molecular mechanisms underlying the activation and subsequent silencing of this program remain elusive. This review will focus on an overlooked aspect associated with ZGA in mice that involves the control over the transient expression of the totipotent-associated transcriptional program. Furthermore, we will discuss the level of conservation of these mechanisms in humans.