EZH1/2 plays critical roles in oocyte meiosis prophase I in mice

Background: Abnormalities in oocyte meiosis can lead to decreased oocyte quality, diminished ovarian reserve, and various female reproductive disorders. Despite their significance, the mechanisms regulating oocyte meiosis, particularly the role of epigenetic regulation, remain poorly understood. In this study, we investigate the role of EZH1/2, a histone methyltransferase responsible for H3K27 trimethylation, in regulating mouse oocyte meiosis by inhibiting its activity and deleting its gene.
Results: In in vitro cultured embryonic ovaries, we found that EZH1/2 is essential for oocyte development during meiosis prophase I in mice. Inhibition of EZH1/2 activity or its genetic knockout led to increased apoptosis and a reduced number of oocytes within the embryonic ovaries. Examination of meiotic marker proteins, including γ-H2AX, MSY2 (a marker for diplotene stage), and SCP1 (a synapsis complex protein), revealed that loss of EZH1/2 function impaired the repair of DNA double-strand breaks (DSBs) and CPI-1205 disrupted meiotic progression in fetal mouse ovaries. Additionally, EZH1/2 deficiency resulted in reduced phosphorylation of ATM (Ataxia Telangiectasia Mutated kinase) and a decrease in the expression of key DNA repair proteins, such as Hormad1, Mre11, Rad50, and Nbs1, further highlighting EZH1/2′s crucial role in initiating DNA repair. RNA sequencing analysis demonstrated that the deletion of EZH1/2 caused aberrant expression of genes involved in various aspects of oocyte development in embryonic ovaries. Furthermore, knockout of EZH1/2 altered the levels of H3K9me3 and H4K20me2, as well as the expression of their target genes, L3mbtl4 and Fbxo44.
Conclusions: Our study reveals that EZH1/2 plays a critical role in DSB repair during oocyte meiosis prophase I through multiple mechanisms. These findings provide new insights into the epigenetic regulation of oocyte development and highlight the importance of histone modifications in fetal oocyte maintenance and female fertility.