Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
Department of Cardiology, Union Hospital, and Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
Nat Commun. 2022 Mar 18;13(1):1469. doi: 10.1038/s41467-022-28990-6.
N6-methyladenosine (mA) is the most prevalent RNA modification at the posttranscriptional level and involved in various diseases and cellular processes. However, the underlying mechanism of mA regulation in intervertebral disc degeneration (IVDD) remains elusive. Here, we show that methylation of the lncRNA NORAD significantly increases in senescent nucleus pulposus cells (NPCs) by mA sequencing. Subsequent loss- and gain-of-function experiments reveal WTAP is increased in senescent NPCs due to an epigenetic increase in H3K4me3 of the promoter mediated by KDM5a, and significantly promotes NORAD mA modification. Furthermore, YTHDF2-mediated decay of NORAD is enhanced in senescent NPCs, and then deficiency of NORAD results in less sequestraion of PUMILIO proteins, contributing to the augmented activity of PUM1/2, thus repressing the expression of target E2F3 mRNAs and promoting the cellular senescence. Here, we show interruption of NORAD mA modification or the NORAD/PUMILIO/E2F3 axis could serve as a potential therapeutic target to inhibit the senescence of NPCs and development of IVDD.
N6-甲基腺苷（m6A）是最普遍的转录后水平的 RNA 修饰，参与各种疾病和细胞过程。然而，m6A 在椎间盘退变（IVDD）中的调节机制仍不清楚。在这里，我们通过 m6A 测序显示，长非编码 RNA NORAD 的甲基化在衰老的核髓核细胞（NPC）中显著增加。随后的缺失和功能获得实验表明，WTAP 由于 KDM5a 介导的启动子 H3K4me3 的表观遗传增加而在衰老的 NPC 中增加，并显著促进 NORAD m6A 修饰。此外，NORAD 在衰老的 NPC 中 YTHDF2 介导的降解增强，随后 NORAD 的缺乏导致 PUMILIO 蛋白的隔离减少，导致 PUM1/2 的活性增加，从而抑制靶 E2F3 mRNA 的表达并促进细胞衰老。在这里，我们表明，阻断 NORAD m6A 修饰或 NORAD/PUMILIO/E2F3 轴可以作为抑制 NPC 衰老和 IVDD 发展的潜在治疗靶点。
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