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

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.