GSE178232
Zygotic genome activation by the totipotency pioneer factor Nr5a2 [CUT&Tag]
Life begins with a switch in genetic control from the maternal to the embryonic genome during zygotic genome activation (ZGA). Despite its importance, the essential regulators of ZGA remain largely unknown in mammals. Based on de novo motif searches, we identified the orphan nuclear receptor Nr5a2 as a key activator of major ZGA in mouse 2-cell embryos. Nr5a2 is required for progression beyond the 2-cell stage. It binds to its motif within SINE B1/Alu retrotransposable elements found in cis-regulatory regions of ZGA genes. Chemical inhibition suggests that 72% of ZGA genes are regulated by Nr5a2 and potentially other orphan nuclear receptors. Nr5a2 promotes chromatin accessibility during ZGA and binds nucleosomal DNA in vitro. We conclude that Nr5a2 is an essential pioneer factor that regulates ZGA. Overall design: CUT&Tag of H3K4me3 was performed on GV-stage oocytes for validation of CUT&Tag experiments in 2-cell embryos. Nr5a2 CUT&Tag on 2C-embryos was performed with normal high salt condition (300 mM NaCl). Esrrb CUT&Tag on 2C-embryo was performed with low salt condition (150 mM NaCl) due to its low binding affinity to the genome.