母体组蛋白甲基转移酶通过调节组蛋白和DNA修饰对哺乳动物胚胎的表观遗传调控和发育至关重要。这里,我们通过揭示母体Ezh1/2缺失对MII卵母细胞和小鼠早期胚胎线粒体的关键影响,报道了一种新机制。我们发现小鼠MII卵母细胞的Ezh1/2敲除会损害线粒体的结构并减少其数量,线粒体膜电位和呼吸功能增强。Ezh1/2缺失的类似效果已经在2细胞和桑态度胚观察到,表明母体Ezh1/2缺乏对线粒体的影响扩展到早期胚胎。然而,母亲Ezh1/2的损失导致了严重的桑兰缺陷:数量,膜电位,呼吸功能,线粒体的ATP产量显著下降。MII卵母细胞和早期胚胎中活性氧的含量均升高,提示母体Ezh1/2基因敲除诱导氧化应激。此外,母体Ezh1/2消融干扰了桑胚和胚泡胚胎的自噬。最后,母体Ezh1/2缺失导致小鼠胚泡胚胎细胞凋亡。通过分析基因表达谱,我们发现母体Ezh1/2敲除影响MII卵母细胞和早期胚胎线粒体相关基因的表达。染色质免疫沉淀-聚合酶链反应分析表明Ezh1/2直接调控基因Fxyd6、Adpgk、Aurkb,Zfp521,Ehd3,Sgms2,Pygl,Slc1a1和Chst12由H3K27me3修改而成。总之,我们的研究揭示了母体Ezh1/2对卵母细胞和早期胚胎线粒体结构和功能的关键影响,并提出了通过调节线粒体状态对母体早期胚胎发育进行表观遗传调控的新机制。
Maternal histone methyltransferase is critical for epigenetic regulation and development of mammalian embryos by regulating histone and DNA modifications. Here, we reported a novel mechanism by revealing the critical effects of maternal Ezh1/2 deletion on mitochondria in MII oocytes and early embryos in mice. We found that Ezh1/2 knockout in mouse MII oocytes impaired the structure of mitochondria and decreased its number, but membrane potential and respiratory function of mitochondrion were increased. The similar effects of Ezh1/2 deletion have been observed in 2-cell and
morula embryos, indicating that the effects of maternal Ezh1/2 deficiency on mitochondrion extend to early embryos. However, the loss of maternal Ezh1/2 resulted in a severe defect of
morula: the number, membrane potential, respiratory function, and ATP production of mitochondrion dropped significantly. Content of reactive oxygen species was raised in both MII oocytes and early embryos, suggesting maternal Ezh1/2 knockout induced oxidative stress. In addition, maternal Ezh1/2 ablation interfered the autophagy in
morula and blastocyst embryos. Finally, maternal Ezh1/2 deletion led to cell apoptosis in blastocyst embryos in mice. By analyzing the gene expression profile, we revealed that maternal Ezh1/2 knockout affected the expression of mitochondrial related genes in MII oocytes and early embryos. The chromatin immunoprecipitation-polymerase chain reaction assay demonstrated that Ezh1/2 directly regulated the expression of genes Fxyd6, Adpgk, Aurkb, Zfp521, Ehd3, Sgms2, Pygl, Slc1a1, and Chst12 by H3K27me3 modification. In conclusion, our study revealed the critical effect of maternal Ezh1/2 on the structure and function of mitochondria in oocytes and early embryos, and suggested a novel mechanism underlying maternal epigenetic regulation on early embryonic development through the modulation of mitochondrial status.