SETD2 regulates oocytes in vitro maturation through histone methylation and maternal mRNA degradation in yak

In vitro maturation (IVM) of oocytes is a vital aspect of assisted reproductive technology (ART), and its proper application can enhance reproductive efficiency. However, owing to the scarcity of research on the IVM of yak oocytes, its application in yak breeding remains underexplored. Therefore, in this study, we conducted high-throughput mRNA sequencing of immature and mature yak oocytes, which revealed transcriptomic changes during the IVM process in this unique high-altitude domesticated animal. Transcriptomic analysis also identified the histone methyltransferase SET domain-containing 2 (SETD2) as a key factor associated with post-translational modifications during oocyte maturation. To determine the role of SETD2 in oocytes, we employed the SETD2 inhibitor EZM0414 during oocyte maturation. Inhibition of SETD2 resulted in a significant reduction in histone methylation levels, lower oocyte maturation rate in vitro, and suppression of maternal mRNAs degradation suppression (P < 0.05). These findings indicated that SETD2 modulates oocyte maturation by regulating histone methylation and maternal mRNAs degradation. Furthermore, suppression of SETD2 markedly reduced the expression of oocyte secretion-related proteins (TSG6 and GDF9) and cumulus expansion-related protein (PTGS2), demonstrating that oocyte secretion and cumulus expansion were positively correlated with SETD2. Overall, our findings establish SETD2 as an essential regulator of yak oocyte maturation via histone methylation and maternal mRNAs degradation.