Activation of the Maternal Genome Through Asymmetric Distribution of Oocyte-Genome-Associated Histone H3.3

Upon fertilization, the typically silent and epigenetically repressed oocyte genome undergoes activation, yet the precise mechanism remains unclear. The histone variant H3.3 is evenly distributed throughout the oocyte genome, suggesting its involvement in repression. This study reveals that oocyte-genome-associated H3.3 (oH3.3) undergoes asymmetric segregation among four-cell stage blastomeres, persisting in only two blastomeres through the blastocyst stage. These oH3.3-retaining blastomeres maintain a repressive state characterized by high levels of the chromatin marker H3K9me2. Intriguingly, single-cell RNA-seq analysis revealed asymmetric transcriptional activation between paternal and maternal genomes, with the maternal genome being considerably less active. We propose a model wherein oH3.3 and associated oocyte DNA co-segregate during mitosis, allowing two blastomeres to inherit oH3.3 and a strand of oocyte DNA from maternal chromatids. Meanwhile, the other blastomeres acquire newly synthesized DNA associated with the nascent histone H3, which lacks oocyte-specific repressive modifications. Consequently, full maternal genome activation occurs in two of the four-cell stage blastomeres, while the remaining two, which retain oH3.3, remain partially repressed. This study uncovers a previously unrecognized H3.3 mediated mechanism for maternal genome activation. ### Competing Interest Statement The authors have declared no competing interest.