College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
BMC Biol. 2023 Oct 20;21(1):221. doi: 10.1186/s12915-023-01731-x.
Functioning as a competing endogenous RNA (ceRNA) is the main action mechanism of most cytoplasmic lncRNAs. However, it is not known whether this mechanism of action also exists in the nucleus.
We identified four nuclear lncRNAs that are presented in granulosa cells (GCs) and were differentially expressed during sow follicular atresia. Notably, similar to cytoplasmic lncRNAs, these nuclear lncRNAs also sponge miRNAs in the nucleus of GCs through direct interactions. Furthermore, NORSF (non-coding RNA involved in sow fertility), one of the nuclear lncRNA acts as a ceRNA of miR-339. Thereby, it relieves the regulatory effect of miR-339 on CYP19A1 encoding P450arom, a rate-limiting enzyme for E2 synthesis in GCs. Interestingly, miR-339 acts as a saRNA that activates CYP19A1 transcription and enhances E2 release by GCs through altering histone modifications in the promoter by directly binding to the CYP19A1 promoter. Functionally, NORSF inhibited E2 release by GCs via the miR-339 and CYP19A1 axis.
Our findings highlight an unappreciated mechanism of nuclear lncRNAs and show it acts as a ceRNA, which may be a common lncRNA function in the cytoplasm and nucleus. We also identified a potential endogenous saRNA for improving female fertility and treating female infertility.
作为竞争性内源 RNA (ceRNA) 发挥作用是大多数细胞质 lncRNA 的主要作用机制。然而，核内是否存在这种作用机制尚不清楚。
我们鉴定了四个在猪卵泡闭锁过程中在颗粒细胞 (GC) 中呈现且差异表达的核 lncRNA。值得注意的是，与细胞质 lncRNA 相似，这些核 lncRNA 也通过直接相互作用在 GC 的核内海绵吸附 miRNAs。此外，核 lncRNA 之一的 NORSF（与母猪生育力相关的非编码 RNA）作为 miR-339 的 ceRNA。从而，它缓解了 miR-339 对 CYP19A1 编码 P450arom 的调控作用，CYP19A1 编码 P450arom 是 GC 中 E2 合成的限速酶。有趣的是，miR-339 作为一种 saRNA，通过直接结合 CYP19A1 启动子，改变启动子中的组蛋白修饰，激活 CYP19A1 转录，并增强 GC 中 E2 的释放。功能上，NORSF 通过 miR-339 和 CYP19A1 轴抑制 GC 中 E2 的释放。
我们的研究结果强调了核 lncRNA 的一种未被充分认识的机制，并表明其作为 ceRNA 发挥作用，这可能是细胞质和核内普遍存在的 lncRNA 功能。我们还鉴定了一种潜在的内源性 saRNA，可用于提高女性生育能力和治疗女性不孕。
