GABPA regulates zygotic genome activation and pluripotency formation

Mammalian early embryo development incorporates a series of processes including maternal-to-zygotic transition (MZT), zygotic genome activation (ZGA) and lineage specification etc., coupled with totipotency decline and pluripotency formation. Identification of transcription factors (TFs) orchestrating these processes remains challenging. In this study, by taking advantages of targeted protein degron system in mice, which enabled us to study TF stage-specific functions in vivo, we identified and validated the Gabpa is not only a regulator of major ZGA, but also plays an essential role in epiblast lineage specification and pluripotency formation. GABPA together with other reported pluripotency regulators plays major roles in a stepwise manner during the pluripotency formation, highlighting a dynamic multi-factorial pluripotency regulation network throughout mammalian pre-implantation development. In this study, by generating dTAG mice and applying the low-input CUT&RUN technology, we identified and demonstrated that the transcription factor GA repeat binding protein alpha (Gabpa), which is a minor ZGA gene, is a key regulator in naïve pluripotency regulation. Our stage-specific degradation results revealed that GABPA is not only important for major ZGA, but also critical for ICM to naïve pluripotency transition by regulating numerous pluripotency genes.