NFYA regulates two sequential genome-wide transcriptional activation events during oocyte to embryo transition

Abstract Primordial follicle oocyte activation (PFA) and zygotic genome activation (ZGA) represent two major waves of transcription activation respectively required for oocyte growth and preimplantation embryo development. Although many shared molecular hallmarks between PFA and ZGA suggest potential common factors and mechanisms driving both waves of transcriptional activation, such factors are yet to be identified. Here we demonstrate that the pioneer factor NFYA belongs to such regulators. Oocyte-specific Nfya deletion impairs open chromatin establishment and transcriptional activation during PFA, which triggers non-canonical ferroptosis leading to early folliculogenesis failure. Moreover, acute NFYA depletion in zygotes causes defective ZGA and predominantly two-cell embryo arrest. Mechanistically, although NFYA exhibits distinct chromatin-binding preferences predominantly targeting promoters during PFA and enhancers during ZGA, pre-occupied NFYA regulates chaperones and histone genes in both PFA and ZGA through conserved promoter binding. Together, our studies establish NFYA as a multifaceted regulator of genome activation during both PFA and ZGA. Highlights NFYA deficiency impairs primordial follicle oocyte activation (PFA) and triggers non-canonical ferroptosis resulting in early folliculogenesis failure NFYA depletion impairs zygotic genome activation (ZGA) and causes predominantly 2-cell embryo arrest Conserved and distinct NFYA-chromatin interactions drive both PFA and ZGA Chaperones are pre-occupied and regulated by NFYA and their inhibition impairs both PFA and ZGA. Competing Interest Statement The authors have declared no competing interest.