Zygotic Splicing Activation of the Transcriptome is a Crucial Aspect of Maternal‐to‐Zygotic Transition and Required for the Conversion from Totipotency to Pluripotency

Abstract During maternal‐to‐zygotic transition (MZT) in the embryo, mRNA undergoes complex post‐transcriptional regulatory processes. However, it is unclear whether and how alternative splicing plays a functional role in MZT. By analyzing transcriptome changes in mouse and human early embryos, dynamic changes in alternative splicing during MZT are observed and a previously unnoticed process of zygotic splicing activation (ZSA) following embryonic transcriptional activation is described. As the underlying mechanism of RNA splicing, splicing factors undergo dramatic maternal‐to‐zygotic conversion. This conversion relies on the key maternal factors BTG4 and PABPN1L and is zygotic‐transcription‐dependent. CDK11‐dependent phosphorylation of the key splicing factor, SF3B1, and its aggregation with SRSF2 in the subnuclear domains of 2‐cell embryos are prerequisites for ZSA. Isoforms generated by erroneous splicing, such as full‐length Dppa4 , hinder normal embryonic development. Moreover, alternative splicing regulates the conversion of early embryonic blastomeres from totipotency to pluripotency, thereby affecting embryonic lineage differentiation. ZSA is an essential post‐transcriptional process of MZT and has physiological significance in generating new life. In addition to transcriptional activation, appropriate expression of transcript isoforms is also necessary for preimplantation embryonic development.