H4K20me3 erasure facilitates reprogramming to totipotent-like state by promoting DUX4 mediated transcription

Epigenetic remodeling following fertilization is essential for the acquisition of embryonic totipotency. The role of H4K20me3, a key epigenetic modification, remains largely unexplored in the context of early human embryogenesis. Here, we observed a dynamic erasure of H4K20me3 modification during zygotic genome activation (ZGA), followed by a re-establishment after ZGA in human embryos. Using in vitro reprogramming to totipotent-like states, we demonstrated that transient removal of H4K20me3 in human embryonic stem cells promotes DUX4-mediated expression of totipotent genes and facilitates the transition into a totipotent-like state. Mechanistically, we show that H4K20me3 preferentially accumulates around genes specific to the 8-cell-like state, which are induced by DUX4 and repressed by H4K20me3 modification. Furthermore, H4K20me3 enrichment near pericentromeric regions may regulate satellite repeat transcripts, which have been shown to participate in heterochromatin remodeling and totipotency reprogramming. Our findings suggest that active erasure of H4K20me3 at the human ZGA stage plays a role in facilitating the expression of totipotency genes, thereby reinforcing early human embryo development.