Tang Minyue, Bai Long, Wan Zhe, Wan Shan, Xiang Yu, Qian Yeqing, Cui Long, You Jiali, Hu Xiaoling, Qu Fan, Zhu Yimin
Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
Key Laboratory of Reproductive Genetics (Ministry of Education) and Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
Mol Ther Nucleic Acids. 2021 Jun 24;26:1433-1445. doi: 10.1016/j.omtn.2021.06.012. eCollection 2021 Dec 3.
Unexplained recurrent spontaneous abortion (URSA) is one of the most intractable clinical challenges in reproduction. As a specific type of endogenous non-coding RNA, circular RNAs (circRNAs) have great pre-clinical diagnostic and therapeutic values in diseases. Recently, thousands of circRNAs were detected in human pre-implantation embryos, indicating that circRNAs potentially have important regulatory functions. However, the roles of circRNAs in URSA remain largely unknown. In this study, we elucidated deregulated circRNA expression and distinct competing endogenous RNA (ceRNA) networks by comparing URSA placental villus with that of patients with normal pregnancy using microarrays. We characterized a distinct circRNA, circRNA-0050703, which is downregulated in URSA placental villus (thus we named it circRNA-DURSA). Silencing of circRNA-DURSA results in trophoblast cell apoptosis . Furthermore, mechanistic dissection revealed that circRNA-DURSA exerts its effects by competitively binding to miR-760, which post-transcriptionally targets HIST1H2BE. Additionally, after circRNA-DURSA silencing , the numbers of implanted embryos decreased significantly. These results reveal the regulatory roles of circRNA-DURSA in trophoblasts and identified a distinct circRNA-DURSA/miR-760/HIST1H2BE axis as potentially important diagnostic and therapeutic targets for URSA treatment.
不明原因复发性自然流产（URSA）是生殖领域最棘手的临床挑战之一。作为一种特殊类型的内源性非编码RNA，环状RNA（circRNA）在疾病的临床前诊断和治疗中具有重要价值。最近，在人类植入前胚胎中检测到数千种circRNA，这表明circRNA可能具有重要的调控功能。然而，circRNA在URSA中的作用仍 largely unknown。在本研究中，我们通过使用微阵列比较URSA胎盘绒毛与正常妊娠患者的胎盘绒毛，阐明了circRNA表达失调和不同的竞争性内源性RNA（ceRNA）网络。我们鉴定了一种独特的circRNA，circRNA-0050703，它在URSA胎盘绒毛中表达下调（因此我们将其命名为circRNA-DURSA）。沉默circRNA-DURSA会导致滋养层细胞凋亡。此外，机制分析表明，circRNA-DURSA通过竞争性结合miR-760发挥作用，miR-760在转录后靶向HIST1H2BE。此外，circRNA-DURSA沉默后，着床胚胎的数量显著减少。这些结果揭示了circRNA-DURSA在滋养层细胞中的调控作用，并确定了独特的circRNA-DURSA/miR-760/HIST1H2BE轴作为URSA治疗潜在的重要诊断和治疗靶点。
