The chromatin remodeler Snf2h is essential for oocyte meiotic cell cycle progression

Oocytes are indispensable for mammalian life. Thus, it is important to understand how mature oocytes are generated. As a critical stage of oocytes development, meiosis has been extensively studied, yet how chromatin remodeling contributes to this process is largely unknown. Here, we demonstrate that the ATP-dependent chromatin remodeling factor Snf2h (also known as Smarca5) plays a critical role in regulating meiotic cell cycle progression. Females with oocyte-specific depletion of Snf2h are infertile and oocytes lacking Snf2h fail to undergo meiotic resumption. Mechanistically, depletion of Snf2h results in dysregulation of meiosis-related genes, which causes failure of maturation-promoting factor (MPF) activation. ATAC-seq analysis in oocytes revealed that Snf2h regulates transcription of a key meiotic gene, Prkar2b, by increasing its promoter chromatin accessibility. Our studies thus not only demonstrate the importance of Snf2h in oocyte meiotic resumption, but also reveal the mechanism underlying how a chromatin remodeling factor can regulate oocyte meiosis. RNA-seq were performed for Snf2h WT and KO oocytes at different developmental stages [i.e., Growing1 (40-45um), Growing2 (50-55um), Fully-grown oocytes (>70um)]. For each stage, two RNA-seq replicates were performed for each group. For FGO, oocytes were collected without or with prior hormon stimulation, which are referred to as non-hormone stimulated FGO (nFGO) and FGO, respectively. Two ATAC-seq replicates were performed in Growing1 and fully grown oocytes from both Snf2h WT and conditional KO female mice.卵母细胞对于哺乳动物生命活动不可或缺，因此阐明成熟卵母细胞的生成机制具有重要意义。作为卵母细胞发育的关键阶段，减数分裂已得到广泛研究，但染色质重塑如何调控这一过程仍尚不明确。 本研究证实，ATP依赖型染色质重塑因子Snf2h（又名Smarca5）在调控减数分裂细胞周期进程中发挥关键作用。卵母细胞特异性敲除Snf2h的雌性小鼠不育，且缺失Snf2h的卵母细胞无法完成减数分裂恢复。机制层面上，Snf2h的敲除会导致减数分裂相关基因表达失调，进而使成熟促进因子（maturation-promoting factor, MPF）无法激活。对卵母细胞的ATAC-seq分析显示，Snf2h可通过提高关键减数分裂基因Prkar2b启动子区域的染色质可及性，调控其转录。因此，本研究不仅阐明了Snf2h在卵母细胞减数分裂恢复中的重要作用，还揭示了染色质重塑因子调控卵母细胞减数分裂的潜在机制。 本研究对不同发育阶段的Snf2h野生型（Wild Type, WT）与敲除型（Knockout, KO）卵母细胞开展了RNA测序（RNA-seq），发育阶段包括生长1期（Growing1，40-45μm）、生长2期（Growing2，50-55μm）以及完全成熟卵母细胞（Fully-grown oocytes, FGO，直径>70μm）。每个阶段的每个组别均设置2次RNA测序生物学重复。对于FGO，分别收集未经过激素刺激与预先经过激素刺激的卵母细胞，分别命名为非激素刺激FGO（non-hormone stimulated FGO, nFGO）与FGO。本研究在Snf2h野生型与条件性敲除雌性小鼠的生长1期及完全成熟卵母细胞中，各设置2次ATAC-seq生物学重复。