The RNA ac4C writer NAT10-dependent post-transcriptional regulations are prerequisites for zygotic splicing activation in mouse

Abstract Programmed establishment of the zygote epitranscriptome orchestrates epitranscriptome fidelity and developmental potency acquisition during mammalian preimplantation embryogenesis. N4-acetylcytidine (ac 4 C) is a conserved RNA modification catalyzed by N-acetyltransferase 10 (NAT10), the currently established mammalian RNA ac 4 C writer, but its maternal function during the maternal-to-zygotic transition remains incompletely understood. In this study, we found that oocyte-specific Nat10 ablation from primary follicle stage causes female infertility with embryonic developmental arrest predominantly at the 2-cell stage. Notably, the maternal protein NAT10 is essential for ac 4 C deposition on zygotic genome activation (ZGA) transcripts and maternal mRNAs, and the loss of Nat10 can lead to abnormal accumulation of maternal transcripts and major ZGA inactivation. By interrogating ac 4 C LACE-seq, RNA-seq, and Ribo-lite data, we identify splicing-factor transcripts as prominent NAT10-associated ac 4 C targets whose mRNA abundance and ribosome occupancy are reduced after maternal Nat10 deletion. These molecular changes are accompanied by impaired nuclear speckle organization and widespread disruption of detectable alternative-splicing events during zygotic splicing activation. Together, our findings demonstrate that the RNA ac 4 C writer NAT10 is essential for the post-transcriptional regulation of mouse zygotic splicing activation and provide valuable view for further exploration of the epigenetic mechanism during maternal-to-zygotic transition.