Nr5a2 is dispensable for ZGA but essential for morula development [ATAC-seq]

Early embryogenesis is driven by transcription factors (TFs) that first activate the zygotic genome and then specify the lineages constituting the blastocyst. While the TFs specifying the blastocyst's lineages are well characterised, those playing earlier roles are ill-defined. Using mouse models of the TF Nr5a2, we show that Nr5a2-/- embryos arrest at the early morula stage and exhibit overt phenotypical problems such as altered lineage specification, frequent mitotic failure and substantial chromosome segregation defects. We further show that whilst NR5A2 plays a minor but measurable role during zygotic genome activation, it predominantly acts as a master regulator at the 8-cells stage, controlling expression of lineage-specifying TFs and genes involved in mitosis, telomere maintenance and DNA repair. We conclude that NR5A2 coordinates proliferation, genome stability and lineage specification to ensure proper morula development. Overall design: ATAC-seq reactions were performed ex-vivo on 8-cell stage embryos for maternal and zygotic Nr5a2 KO samples. Instead, embryos from Inducible NrKO samples (iNrko) were dissected at the early 2C stage (30h post hCG), and kept in culture for additional 45h (until they reached the 8C stage) before processing, treating or not with 750nM 4-hydroxytamoxifen for the first 24h.