Fig. 7. NR5A2 connects ZGA to the first lineage specification in early development.

During mouse early development, NR5A2, a NR TF highly induced during ZGA, predominantly binds B1 repeats. NR5A2 is not required for global ZGA and enhancer opening in 2C embryos, but critically regulates 4–8C transcription (mid-preimplantation gene activation) and enhancer opening in 8C embryos. In 8C embryos, its targets include not only key pluripotency genes such as Pou5f1 and Nanog, but also PrE genes such as Gata6,  and key TE genes such as Tead4, Gata3. For early ICM genes, NR5A2 opens regulatory regions at the 8C stage, which likely also provides binding sites for NSO at late stages (blastocyst and mESC). NSO bind and regulate both early and late ICM genes in mESCs. Therefore, NR5A2 functions in totipotent embryos to bridge ZGA to the first lineage specification.