RNA-Seq Facilitates Quantitative Analysis of Wild Type and Bnc1tr/tr oocyte Transcriptomes

Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by premature exhaustion of primordial follicles. POI causes infertility, serious daily life disturbances and long-term health risks. However, the underlying mechanism remains largely unknown. We have previously identified Basonuclin1 (BNC1) mutation from a large Chinese POI pedigree and find the targeted Bnc1 mutation mouse exhibites POI. In this study, we find that BNC1 plays a key role in the dynamic balance of ovarian reserve, and maintaining lipid metabolism and redox homeostasis in oocytes during follicular development. Deficiency of BNC1 results in premature follicular activation and accelerated follicular atresia, but doesn't affect the ovarian primordial follicle reserve. Mechanistically, BNC1 targets the NF2-YAP pathway to trigger oocyte ferroptosis. Inhibition of ferroptosis significantly rescues POI. These findings uncover a novel pathologic mechanism of POI based on BNC1 deficiency and is the first report showing ferroptosis involved in oocyte death. Oocyte mRNA profiles of 12-weeks old wild type (WT) and Bnc1tr/tr mice早发性卵巢功能不全（Primary ovarian insufficiency, POI）是一类以原始卵泡过早耗竭为特征的卵巢功能异常临床综合征。POI可引发不孕、严重的日常生活障碍以及长期健康风险，但其具体发病机制目前仍未被完全阐明。此前我们从一个大型中国POI家系中鉴定出Basonuclin1（BNC1）突变，并发现靶向构建Bnc1突变的小鼠可出现POI表型。本研究发现，BNC1在卵泡发育过程中，对卵巢储备的动态平衡、卵母细胞的脂质代谢与氧化还原稳态的维持均发挥关键作用。BNC1缺失会导致卵泡过早激活与卵泡闭锁加速，但不会影响卵巢原始卵泡储备。机制层面，BNC1通过靶向调控NF2-YAP通路诱发卵母细胞铁死亡（ferroptosis）；抑制铁死亡可显著改善POI表型。本研究揭示了一种基于BNC1缺失的POI全新病理机制，同时也是首项证实铁死亡参与卵母细胞死亡的研究报道。本次研究的检测样本为12周龄野生型（wild type, WT）与Bnc1tr/tr突变小鼠的卵母细胞mRNA表达谱。