WTAP-mediated m6A modification of lncRNA NORAD promotes intervertebral disc degeneration

• Published in: Nature communications Vol. 13; no. 1; p. 1469
• Main Authors: Li, Gaocai, Ma, Liang, He, Shujie, Luo, Rongjin, Wang, Bingjin, Zhang, Weifeng, Song, Yu, Liao, Zhiwei, Ke, Wencan, Xiang, Qian, Feng, Xiaobo, Wu, Xinghuo, Zhang, Yukun, Wang, Kun, Yang, Cao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18-03-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/31; 13/89; 14/1; 14/63; 45/91; 49/15; 59/57; 631/337/1645/2570; 631/337/176; 631/337/384/2568; 631/80/304; 631/80/509; 64/60; 96/31; Degeneration; Degenerative disc disease; Epigenetics; Humanities and Social Sciences; Intervertebral discs; Low back pain; multidisciplinary; N6-methyladenosine; Non-coding RNA; Nuclei (cytology); Nucleus pulposus; Post-transcription; RNA modification; Science; Science (multidisciplinary); Senescence; Sequences; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-28990-6

N6-methyladenosine (m
6
A) is the most prevalent RNA modification at the posttranscriptional level and involved in various diseases and cellular processes. However, the underlying mechanism of m
6
A 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 m
6
A 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 m
6
A 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 m
6
A modification or the NORAD/PUMILIO/E2F3 axis could serve as a potential therapeutic target to inhibit the senescence of NPCs and development of IVDD.
Intervertebral disc degeneration (IVDD) is the leading cause of low back pain and Nucleus pulposus cell senescence contributes a lot to its progression. Here, the authors reveal WTAP-mediated m6A modification of lncRNA NORAD promotes IVDD.