The Landscape and Regulation of Histone Crotonylation in Mammalian Gametes and Early Embryos

Histone crotonylation is a newly recognized epigenetic modification implicated in transcriptional regulation, cell-fate determination, and disease. However, its dynamics and regulation during mammalian gametes and early embryonic development remain largely unknown. Here, we apply an optimized ULI-NChIP-seq to establish a high-resolution landscape of H3K18 crotonylation (H3K18cr), a representative histone crotonylation mark, in mouse gametes and preimplantation embryos. We report that H3K18cr is enriched in sperm but largely absent in MII oocyte, and undergoes striking reprogramming after fertilization. Maternal-biased parental asymmetry is strongest at the zygote stage and becomes balanced as development progresses. Paternal- and maternal-specific H3K18cr occupy distinct genomic regions with divergent biological functions. Interestingly, H3K18cr undergoes a global transition from broad domains to narrow peaks at minor ZGA stage. This reprogramming is strictly dependent on minor ZGA, but essential for major ZGA and embryonic development. Inhibiting histone deacetylase activity of the HDAC1 complex not only enhances histone acetylation signal, but also impairs the broad-to-narrow transition of histone crotonylation, revealing functional cross-talk between histone crotonylation and acetylation. Following reprogramming, canonical narrow H3K18cr signals can potentially influence gene expression, first-lineage differentiation, and blastocyst development. Collectively, histone crotonylation undergoes extensive reprogramming during early embryogenesis, and its interplay with ZGA links epigenetic regulation to development.