Center for Reproductive Medicine & Fertility Preservation Program, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.
The Center of Reproductive Medicine, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
J Ovarian Res. 2023 Feb 18;16(1):41. doi: 10.1186/s13048-023-01115-3.
Premature ovarian insufficiency (POI) is one of the common women reproductive endocrine diseases which adversely impacts female fertility, but the etiology and pathogenesis still remain elusive. Recently increasing researches focus on the roles of lncRNA in POI. LncRNA DANCR was involved in cell differentiation and multiple cancers. It's highly expressed in ovary while the role of DANCR in POI is still unknown.
Here, we identify a new POI related lncRNA DANCR, which negatively contributes to ovarian granulosa cells aging and follicular atresia. DANCR is proved to be decreasingly expressed in POI patients' granulosa cells. Additionally, Dancr knockout (Dancr) mice were constructed and characterized with POI phenotypes and fertility decline, compared with Dancr mice. Further, in vitro experiments indicated that DANCR knockdown in granulosa cells led to cell aging and series of aging-related changes including proliferation inhibition, cell cycle G1 arrest and DNA damage. Mechanism research revealed DANCR binds with hNRNPC and p53, while DANCR knockdown attenuates the binding of hNRNPC and p53, thus enhancing protein level of p53 and promoting granulosa cells aging significantly.
The newly identified lncRNA DANCR inhibits p53-dependent granulosa cells aging by regulating hNRNPC-p53 interaction, and eventually counteracting POI. This provides new insights into the pathogenesis of POI and provides a potential target for future diagnosis and treatment.
卵巢早衰（POI）是常见的女性生殖内分泌疾病之一，对女性生育能力有不良影响，但病因和发病机制仍不清楚。最近越来越多的研究关注长非编码 RNA（lncRNA）在 POI 中的作用。lncRNA DANCR 参与细胞分化和多种癌症。它在卵巢中高表达，而 DANCR 在 POI 中的作用尚不清楚。
本研究鉴定了一种新的与 POI 相关的 lncRNA DANCR，它对卵巢颗粒细胞衰老和卵泡闭锁起负性作用。DANCR 在 POI 患者的颗粒细胞中表达下调。此外，构建了 Dancr 敲除（Dancr）小鼠，并对其进行了特征分析，发现其表现出 POI 表型和生育力下降，与 Dancr 小鼠相比。进一步的体外实验表明，DANCR 在颗粒细胞中的敲低导致细胞衰老和一系列衰老相关变化，包括增殖抑制、细胞周期 G1 期阻滞和 DNA 损伤。机制研究表明 DANCR 与 hNRNPC 和 p53 结合，而 DANCR 敲低减弱了 hNRNPC 和 p53 的结合，从而显著增强了 p53 的蛋白水平，促进了颗粒细胞的衰老。
新鉴定的 lncRNA DANCR 通过调节 hNRNPC-p53 相互作用抑制 p53 依赖性颗粒细胞衰老，最终拮抗 POI。这为 POI 的发病机制提供了新的见解，并为未来的诊断和治疗提供了潜在的靶点。
