NR5A2 connects genome activation to the first lineage segregation in early mouse development

After fertilization, zygotic genome activation (ZGA) marks the beginning of the embryonic program for a totipotent embryo, which further gives rise to the pluripotent embryonic lineages and extraembryonic trophectoderm after the first lineage commitment. While much has been learned about pluripotency regulation, how ZGA is connected to the pluripotency commitment in early embryos remains elusive. Here, we investigated the role of nuclear receptor 1 family transcription factors (TFs) in mouse pre-implantation embryos, whose motifs are highly enriched in accessible chromatin at the 2-cell (2C) to 8-cell (8C) stages after ZGA. We found NR5A2, an NR TF highly induced upon ZGA, is required for early development, as both the knockdown and knockout of Nr5a2 from 1C embryos led to morula arrest. While the zygotic genome was largely activated at the 2C stage, 4-8C-specific gene activation (mid-preimplantation activation) was substantially impaired. Genome-wide chromatin binding and RNA-seq analyses showed NR5A2 preferentially regulates its binding targets including a subset of key pluripotency genes (i.e., Nanog, Pou5f1, and Tdgf1). Finally, NR5A2-occupied sites at the 2C and 8C stages predominantly reside in accessible B1 elements where its motif is embedded. Taken together, these data identify NR5A2 as a key regulator that connects ZGA to the first lineage segregation in early mouse development.