State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 211166, Nanjing, China.
Department of Microbiology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, 211166, Nanjing, China.
Cell Death Dis. 2021 May 25;12(6):540. doi: 10.1038/s41419-021-03831-4.
The fecundity of female mammals is resolved by the limited size of the primordial follicle (PF) pool formed perinatally. The establishment of PF pool is accompanied by a significant programmed oocyte death. Long non-coding RNAs (lncRNA) are central modulators in regulating cell apoptosis or autophagy in multiple diseases, however, the significance of lncRNAs governing perinatal oocyte loss remains unknown. Here we find that Yin-Yang 1 (YY1) directly binds to the lncRNA X-inactive-specific transcript (Xist) promoter and facilitates Xist expression in the perinatal mouse ovaries. Xist is highly expressed in fetal ovaries and sharply downregulated along with the establishment of PF pool after birth. Gain or loss of function analysis reveals that Xist accelerates oocyte autophagy, mainly through binding to pre-miR-23b or pre-miR-29a in the nucleus and preventing the export of pre-miR-23b/pre-miR-29a to the cytoplasm, thus resulting in decreased mature of miR-23b-3p/miR-29a-3p expression and upregulation miR-23b-3p/miR-29a-3p co-target, STX17, which is essential for timely control of the degree of oocyte death in prenatal mouse ovaries. Overall, these findings identify Xist as a key non-protein factor that can control the biogenesis of miR-23b-3p/miR-29a-3p, and this YY1-Xist-miR-23b-3p/miR-29a-3p-STX17 regulatory axis is responsible for perinatal oocyte loss through autophagy.
哺乳动物的繁殖力取决于围产期形成的原始卵泡（PF）池的有限大小。PF 池的建立伴随着大量程序化的卵母细胞死亡。长链非编码 RNA（lncRNA）是调节多种疾病中细胞凋亡或自噬的核心调节剂，然而，lncRNA 控制围产期卵母细胞丢失的意义尚不清楚。在这里，我们发现 Yin-Yang 1 (YY1) 直接与 lncRNA X 失活特异性转录物（Xist）启动子结合，促进围产期小鼠卵巢中 Xist 的表达。Xist 在胎儿卵巢中高表达，并在出生后随着 PF 池的建立而急剧下调。功能获得或缺失分析表明，Xist 加速卵母细胞自噬，主要通过在核内结合 pre-miR-23b 或 pre-miR-29a，并防止 pre-miR-23b/pre-miR-29a 输出到细胞质，从而导致成熟的 miR-23b-3p/miR-29a-3p 表达减少和 miR-23b-3p/miR-29a-3p 共同靶标 STX17 的上调，这对于控制产前小鼠卵巢中卵母细胞死亡程度的时机至关重要。总的来说，这些发现确定了 Xist 是一种关键的非蛋白因子，可以控制 miR-23b-3p/miR-29a-3p 的生物发生，而 YY1-Xist-miR-23b-3p/miR-29a-3p-STX17 调节轴通过自噬负责围产期卵母细胞丢失。
