p300/CBP inhibition promotes apoptosis in mouse embryos by impairing H1K75ac-mediated DNA repair from the 4-cell to blastocyst stage

Defective pre-implantation embryonic development is a major cause of implantation failure and early embryonic arrest. p300/CBP is known to influence blastocyst formation; nevertheless, its molecular regulatory cascades mediating murine embryonic development from the 4-cell to blastocyst stage are poorly understood. Here, we show that pharmacological inhibition of p300/CBP markedly reduced morula and blastocyst rate, increased embryonic fragmentation, and disrupted markers of compaction, polarization, and first lineage segregation from the 4-cell to blastocyst stage. Smart-seq2 analysis showed that differentially expressed genes were enriched in pathways related to apoptosis, cell-cycle regulation, DNA modification, and embryonic development. Consistently, immunofluorescence analyses showed that p300/CBP inhibition increased apoptosis, suppressed cell proliferation, and promoted DNA damage accumulation. Mechanistically, p300/CBP inhibition reduced histone H1 lysine 75 acetylation (H1K75ac), leading to impaired DNA repair and subsequent activation of p38 signaling, thereby triggering apoptosis. Collectively, our findings identify a p300/CBP-H1K75ac-DNA repair-p38 MAPK signaling axis that maintains genome integrity and developmental competence in mouse pre-implantation embryos.