The establishment of naïve pluripotency is a continuous process starting with the generation of inner cell mass (ICM) which then differentiating into epiblast (EPI). Recent studies have revealed key transcription factors (TFs) for ICM formation, but which TFs initiate EPI specification remains unknown. Polycomb silencing plays an important role in body patterning during embryonic development. PcG proteins form at least two biochemically distinct protein complexes PRC1 and PRC2 that harbor enzymatic activities for H2AK119ub1 and H3K27me3, respectively. Traditional mouse genetic studies showed that KO of the key components of PRC2 cause gastrulation defects, and thus it is believed that PRC2 is not involved in EPI specification. However, the traditional KO approach cannot rule out a maternal effect that might mask its role in preimplantation development.
The development of the protein degradation degron system allows the study of protein function without the interference of maternal effect. By integrating transcriptome and chromatin accessibility during mouse naïve pluripotent stem cell specification, we identified and demonstrated that the transcription factor GABPA is not only a regulator of major ZGA, but also a master EPI specifier required for naïve pluripotency establishment during E3.5 to E4.5 transition using the dTAG protein degradation system. Similarly, we generated a dTAG protein degradation system targeting Eed, a core component of PRC2. To our surprise, Eed degradation affects EPI formation and preimplantation development. Our studies reveal that GABPA and PRC2 are both important for naïve pluripotent stem cell formation.