Chromatin Modifier EP400 Regulates Oocyte Quality and Zygotic Genome Activation in Mice

Epigenetic modifiers that accumulate in oocytes, play a crucial role in steering the developmental program of cleavage embryos and initiating life. However, the identification of key maternal epigenetic regulators remains elusive. In the findings, the essential role of maternal Ep400, a chaperone for H3.3, in oocyte quality and early embryo development in mice is highlighted. Depletion of Ep400 in oocytes resulted in a decline in oocyte quality and abnormalities in fertilization. Preimplantation embryos lacking maternal Ep400 exhibited reduced major zygotic genome activation (ZGA) and experienced developmental arrest at the 2-to-4-cell stage. The study shows that EP400 forms protein complex with NFYA, occupies promoters of major ZGA genes, modulates H3.3 distribution between euchromatin and heterochromatin, promotes transcription elongation, activates the expression of genes regulating mitochondrial functions, and facilitates the expression of rate-limiting enzymes of the TCA cycle. This intricate process driven by Ep400 ensures the proper execution of the developmental program, emphasizing its critical role in maternal-to-embryonic transition. Maternal Ep400, a chaperone for H3.3, is required for oocyte quality and early embryo development in mice. Ep400 depletion in oocytes causes oocyte quality decline and fertilization abnormity. In preimplantation embryos, EP400 occupies promoters of major ZGA genes, modulates H3.3 distribution, and promotes transcription elongation. Preimplantation embryos without maternal Ep400 have reduced transcription activity and developmental arrest at 2-to-4-cell stage. image