聚腺苷酸化端粒非编码RNA作为抗衰老的关键治疗靶点,与Zscan4c协同作用以稳定染色体端粒长度。
Polyadenylated Telomeric Noncoding RNA Functions as a Pivotal Therapeutic Target of Anti-Ageing to Stabilize Telomere Length of Chromosomes Collaborating With Zscan4c.
作者信息
Xu Xiaojuan, Chen Zhengju, Wu Wei, Tian Xiaohe
机构信息
Huaxi MR Research Centre (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China.
School of Life Sciences, Hefei Normal University, Hefei, China.
出版信息
Front Pharmacol. 2022 Feb 9;12:822779. doi: 10.3389/fphar.2021.822779. eCollection 2021.
Telomeres are closely associated with the development of cell aging. Shortening or erosion of telomeres will cause cell mortality, suggesting that the maintenance of telomere integrity facilitates cell anti-senescence. However, the mechanism of how to keep the telomere length remains fragmentary. Here, we found that polyadenylated telomeric noncoding RNA (TERRA) can promote the self-renewal when overexpressed in mouse embryonic stem cells (mESCs), implying that TERRA with polyadenylation is critical for mESC maintenance. Further studies revealed that TERRA with a polyadenylated tail plays an important role in the sustenance of telomere length. High-throughput sequencing and quantitative real-time PCR show that zinc finger and SCAN domain containing 4C (Zscan4c) may be a potential target of TERRA. Zscan4c is negatively regulated by TERRA and collaborates with TERRA to stabilize the telomere length of chromosomes in mESCs. Our study not only identifies TERRA as a potential novel factor of telomere length regulation and uncovers the new molecular mechanism of cell anti-aging, but also indicates that Zscan4c could be a key therapeutic target candidate for therapy in dysfunctional chromosome diseases. These data will expand our understanding of the cell fate regulatory network and will be beneficial to drug discovery and theragnostics for antiaging and anticancer therapy in the future.
端粒与细胞衰老的发生密切相关。端粒的缩短或侵蚀会导致细胞死亡,这表明维持端粒完整性有助于细胞抗衰老。然而,关于如何保持端粒长度的机制仍不完整。在这里,我们发现多聚腺苷酸化的端粒非编码RNA(TERRA)在小鼠胚胎干细胞(mESCs)中过表达时可促进自我更新,这意味着具有多聚腺苷酸化的TERRA对mESC的维持至关重要。进一步的研究表明,具有多聚腺苷酸化尾巴的TERRA在维持端粒长度方面起着重要作用。高通量测序和定量实时PCR表明,含锌指和SCAN结构域的4C(Zscan4c)可能是TERRA的一个潜在靶点。Zscan4c受TERRA负调控,并与TERRA协同作用以稳定mESCs中染色体的端粒长度。我们的研究不仅将TERRA鉴定为端粒长度调控的潜在新因子并揭示了细胞抗衰老的新分子机制,还表明Zscan4c可能是功能失调性染色体疾病治疗的关键治疗靶点候选物。这些数据将扩展我们对细胞命运调控网络的理解,并将有利于未来抗衰老和抗癌治疗的药物发现及治疗诊断。