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

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 () and Cao Yang ()
Additional contact information
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

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61486-7

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