DDX1 Methylation Mediated MATR3 Splicing Regulates Intervertebral Disc Degeneration by Initiating Chromatin Reprogramming

ABSTRACT: Low back pain (LBP), often caused by intervertebral disc degeneration (IVDD), poses a major challenge in aging populations. DDX1, an RNA-binding protein, plays key roles in RNA metabolism but its function in IVDD remains unclear. We identify DDX1 as a non-histone substrate of lysine methyltransferase EZH2, which mono-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.

ORGANISM(S): Homo Sapiens

SUBMITTER: Cao Yang  

PROVIDER: PXD064432 | iProX | Thu May 29 00:00:00 BST 2025

REPOSITORIES: iProX