The transcription factor THAP11 is a general regulator of early embryonic polarization.

During mouse embryogenesis, three sequential waves of cell polarization occur in the 8-cell-morula trophectoderm (TE), E3.5-E4.5 primitive endoderm (PrE), and E4.5-E5.5 epiblast (Epi), driving cell fate determination and morphogenic events that lay the foundation for embryonic development. However, it is not clear whether a general regulator that functions in all three waves of polarization exist. Here, we demonstrate that transcriptional factor THAP11 is such a general regulator. Using a novel mouse model combining genetic knockout and an inducible degron system, we demonstrate that stage-specific acute THAP11 depletion causes the failure of the three waves cell polarization, resulting in defective blastocyst formation, PrE maturation, and Epi lumenogenesis, respectively. Mechanistically, THAP11 does not directly regulate pluripotency genes but drive polarization through both stage-specific and conserved chromatin-bindings that commonly activate polarity programs, including Golgi vesicle transport. THAP11 activates polarity genes by promoting chromatin accessibility at their promoters. THAP11, together with stage-specific regulators, sequentially paces the timing of cell polarization. Collectively, our study establishes THAP11 as a general regulator of embryonic morphogenesis.