Reprogramming the genome to totipotency in mouse embryos

•Totipotent embryos provide insight into efficient genome reprogramming of differentiated cells.•Embryonic genome activation (EGA) correlates with the establishment of totipotency.•Epigenetic remodeling for EGA is central to establishment of totipotency.

Despite investigative interest, the artificial derivation of pluripotent stem cells remains inefficient and incomplete reprogramming hinders its potential as a reliable tool in regenerative medicine. By contrast, fusion of terminally differentiated gametes at fertilization activates efficient epigenetic reprogramming to ensure totipotency of early embryos. Understanding the epigenetic mechanisms required for the transition from the fertilized egg to the embryo can improve efforts to reprogram differentiated cells to pluripotent/totipotent cells for therapeutic use. We review recent discoveries that are providing insight into the molecular mechanisms required for epigenetic reprogramming to totipotency in vivo.