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

Gaocai Li, Liang Ma, Shujie He, Rongjin Luo, Bingjin Wang, Weifeng Zhang, Yu Song, Zhiwei Liao, Wencan Ke, Qian Xiang, Xiaobo Feng, Xinghuo Wu, Yukun Zhang, Kun Wang () and Cao Yang ()
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Gaocai Li: Huazhong University of Science and Technology
Liang Ma: Huazhong University of Science and Technology
Shujie He: Huazhong University of Science and Technology
Rongjin Luo: Huazhong University of Science and Technology
Bingjin Wang: Huazhong University of Science and Technology
Weifeng Zhang: Huazhong University of Science and Technology
Yu Song: Huazhong University of Science and Technology
Zhiwei Liao: Huazhong University of Science and Technology
Wencan Ke: Huazhong University of Science and Technology
Qian Xiang: Huazhong University of Science and Technology
Xiaobo Feng: Huazhong University of Science and Technology
Xinghuo Wu: Huazhong University of Science and Technology
Yukun Zhang: Huazhong University of Science and Technology
Kun Wang: Huazhong University of Science and Technology
Cao Yang: Huazhong University of Science and Technology

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract N6-methyladenosine (m6A) is the most prevalent RNA modification at the posttranscriptional level and involved in various diseases and cellular processes. However, the underlying mechanism of m6A 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 m6A 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 m6A 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 m6A modification or the NORAD/PUMILIO/E2F3 axis could serve as a potential therapeutic target to inhibit the senescence of NPCs and development of IVDD.

Date: 2022
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DOI: 10.1038/s41467-022-28990-6

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