IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-28990-6.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-28990-6
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-28990-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Jan M. van Deursen, 2014. "The role of senescent cells in ageing," Nature, Nature, vol. 509(7501), pages 439-446, May.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. José Luis García-Giménez & Salvador Mena-Molla & Francisco José Tarazona-Santabalbina & Jose Viña & Mari Carmen Gomez-Cabrera & Federico V. Pallardó, 2021. "Implementing Precision Medicine in Human Frailty through Epigenetic Biomarkers," IJERPH, MDPI, vol. 18(4), pages 1-17, February.
    2. Ines Sturmlechner & Chance C. Sine & Karthik B. Jeganathan & Cheng Zhang & Raul O. Fierro Velasco & Darren J. Baker & Hu Li & Jan M. Deursen, 2022. "Senescent cells limit p53 activity via multiple mechanisms to remain viable," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. He Cao & Panpan Yang & Jia Liu & Yan Shao & Honghao Li & Pinglin Lai & Hong Wang & Anling Liu & Bin Guo & Yujin Tang & Xiaochun Bai & Kai Li, 2023. "MYL3 protects chondrocytes from senescence by inhibiting clathrin-mediated endocytosis and activating of Notch signaling," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Moore, Patrick V. & Bennett, Kathleen & Normand, Charles, 2017. "Counting the time lived, the time left or illness? Age, proximity to death, morbidity and prescribing expenditures," Social Science & Medicine, Elsevier, vol. 184(C), pages 1-14.
    5. Konstantin Avchaciov & Marina P. Antoch & Ekaterina L. Andrianova & Andrei E. Tarkhov & Leonid I. Menshikov & Olga Burmistrova & Andrei V. Gudkov & Peter O. Fedichev, 2022. "Unsupervised learning of aging principles from longitudinal data," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    6. Kaushik Bhattacharya & Samarpan Maiti & Szabolcs Zahoran & Lorenz Weidenauer & Dina Hany & Diana Wider & Lilia Bernasconi & Manfredo Quadroni & Martine Collart & Didier Picard, 2022. "Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    7. Xu Zhang & Vesselina M. Pearsall & Chase M. Carver & Elizabeth J. Atkinson & Benjamin D. S. Clarkson & Ethan M. Grund & Michelle Baez-Faria & Kevin D. Pavelko & Jennifer M. Kachergus & Thomas A. White, 2022. "Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    8. Sara Rojas-Vázquez & Beatriz Lozano-Torres & Alba García-Fernández & Irene Galiana & Ana Perez-Villalba & Pablo Martí-Rodrigo & M. José Palop & Marcia Domínguez & Mar Orzáez & Félix Sancenón & Juan F., 2024. "A renal clearable fluorogenic probe for in vivo β-galactosidase activity detection during aging and senolysis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Jina Yun & Simon Hansen & Otto Morris & David T. Madden & Clare Peters Libeu & Arjun J. Kumar & Cameron Wehrfritz & Aaron H. Nile & Yingnan Zhang & Lijuan Zhou & Yuxin Liang & Zora Modrusan & Michelle, 2023. "Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28990-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.