长非编码 RNA HCP5 通过转录调控 MSH5 和 YB1 参与 DNA 损伤修复，从而导致卵巢早衰。

Long noncoding RNA HCP5 participates in premature ovarian insufficiency by transcriptionally regulating MSH5 and DNA damage repair via YB1.

机构信息

Center for Reproductive Medicine, Shandong University, Jinan, Shandong 250012, China.

National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China.

出版信息

Nucleic Acids Res. 2020 May 7;48(8):4480-4491. doi: 10.1093/nar/gkaa127.

The genetic etiology of premature ovarian insufficiency (POI) has been well established to date, however, the role of long noncoding RNAs (lncRNAs) in POI is largely unknown. In this study, we identified a down-expressed lncRNA HCP5 in granulosa cells (GCs) from biochemical POI (bPOI) patients, which impaired DNA damage repair and promoted apoptosis of GCs. Mechanistically, we discovered that HCP5 stabilized the interaction between YB1 and its partner ILF2, which could mediate YB1 transferring into the nucleus of GCs. HCP5 silencing affected the localization of YB1 into nucleus and reduced the binding of YB1 to the promoter of MSH5 gene, thereby diminishing MSH5 expression. Taken together, we identified that the decreased expression of HCP5 in bPOI contributed to dysfunctional GCs by regulating MSH5 transcription and DNA damage repair via the interaction with YB1, providing a novel epigenetic mechanism for POI pathogenesis.

迄今为止，早发性卵巢功能不全（POI）的遗传病因已得到充分证实，然而，长非编码 RNA（lncRNA）在 POI 中的作用在很大程度上尚不清楚。在这项研究中，我们在生化 POI（bPOI）患者的颗粒细胞（GC）中鉴定出一个下调表达的 lncRNA HCP5，它损害 DNA 损伤修复并促进 GC 凋亡。在机制上，我们发现 HCP5 稳定了 YB1 与其伴侣 ILF2 之间的相互作用，这可以介导 YB1 转移到 GC 的核内。HCP5 沉默影响了 YB1 进入核内的定位，并减少了 YB1 与 MSH5 基因启动子的结合，从而降低了 MSH5 的表达。总之，我们发现 bPOI 中 HCP5 的表达降低通过与 YB1 的相互作用调节 MSH5 转录和 DNA 损伤修复，导致 GC 功能障碍，为 POI 发病机制提供了一种新的表观遗传机制。