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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Cao Yang, 2022. "WTAP-mediated m6A modification of lncRNA NORAD promotes intervertebral disc degeneration," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28990-6
    DOI: 10.1038/s41467-022-28990-6
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    References listed on IDEAS

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    1. Jan M. van Deursen, 2014. "The role of senescent cells in ageing," Nature, Nature, vol. 509(7501), pages 439-446, May.
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