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DDX1 methylation mediated MATR3 splicing regulates intervertebral disc degeneration by initiating chromatin reprogramming

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  • Dingchao Zhu

    (Huazhong University of Science and Technology)

  • Huaizhen Liang

    (Huazhong University of Science and Technology)

  • Bide Tong

    (Huazhong University of Science and Technology)

  • Zhi Du

    (Huazhong University of Science and Technology)

  • Gaocai Li

    (Huazhong University of Science and Technology)

  • Weifeng Zhang

    (Huazhong University of Science and Technology)

  • Di Wu

    (Huazhong University of Science and Technology)

  • Xingyu Zhou

    (Huazhong University of Science and Technology)

  • Jie Lei

    (Huazhong University of Science and Technology)

  • Xiaoguang Zhang

    (Huazhong University of Science and Technology)

  • Liang Ma

    (Huazhong University of Science and Technology)

  • Bingjin Wang

    (Huazhong University of Science and Technology)

  • Xiaobo Feng

    (Huazhong University of Science and Technology)

  • Kun Wang

    (Huazhong University of Science and Technology)

  • Lei Tan

    (Huazhong University of Science and Technology)

  • Yu Song

    (Huazhong University of Science and Technology)

  • Cao Yang

    (Huazhong University of Science and Technology)

Abstract

Low back pain (LBP), primarily driven by intervertebral disc degeneration (IVDD), has become a core challenge in public health. DDX1, an RNA-binding protein, plays key roles in RNA metabolism but its function in IVDD remains unclear. We identify DDX1 as a substrate of methyltransferase EZH2, which methylates DDX1 at lysine 234 (K234), promoting IVDD in vitro and in vivo. EZH2 inhibition restores matrix homeostasis in nucleus pulposus (NP) cells and slows IVDD progression. Methylation at DDX1 K234 disrupts its interaction with splicing factors and RNA targets, promoting exon 14 skipping in MATR3. This truncated MATR3 disrupts nuclear architecture, increases chromatin accessibility, and activates signaling pathways such as Wnt, leading to NP cell senescence and apoptosis. Notably, delivery of MATR3-L-overexpressing mRNA via cationic lipid nanoparticles reduces NP cell degeneration and significantly alleviates IVDD, offering important insights into IVDD pathogenesis and potential therapeutic strategies.

Suggested Citation

  • Dingchao Zhu & Huaizhen Liang & Bide Tong & Zhi Du & Gaocai Li & Weifeng Zhang & Di Wu & Xingyu Zhou & Jie Lei & Xiaoguang Zhang & Liang Ma & Bingjin Wang & Xiaobo Feng & Kun Wang & Lei Tan & Yu Song , 2025. "DDX1 methylation mediated MATR3 splicing regulates intervertebral disc degeneration by initiating chromatin reprogramming," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61486-7
    DOI: 10.1038/s41467-025-61486-7
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