DDX1 Methylation Mediated MATR3 Splicing Regulates Intervertebral Disc Degeneration by Initiating Chromatin Reprogramming_RIPSEQ
Low back pain (LBP) is considered a critical socio-economic challenge faced by the aging population, largely attributed to intervertebral disc degeneration (IVDD), a prevalent age-related condition. DDX1, an RNA-binding protein, emerges as a central regulator of cellular fate and aging by orchestrating translation initiation, pre-mRNA splicing, mRNA export and decay. However, the role of DDX1 in IVDD remains elusive. Here, we reveal that DDX1 as a non-histone substrate of lysine methyltransferase EZH2, subject to EZH2-mediated mono-methylation at lysine residue 234 (K234), facilitating IVDD in vitro and in vivo. Gain and loss of function assays reveal that EZH2 deficiency restores anabolic-catabolic homeostasis in nucleus pulposus (NP) cells and alleviates IVDD progression. Furthermore, DDX1 interactome analysis indicates that DDX1 K234 methylation weakens its interactions with splicing factors and targeted RNA motifs, promoting exon 14 skipping to produce truncated MATR3. This aberrant form of MATR3 disrupts nuclear organization and architecture maintenance, culminating in excessive chromatin accessibility and hyperactivation of signaling pathways such as Wnt, driving NP cell senescence and apoptosis. Importantly, a cationic lipid nanoparticles-based strategy for delivering MATR3-L-overexpressing mRNA cargo efficiently diminished NP cells senescence and apoptosis, and substantially mitigated IVDD progression, suggesting promising targets and effective approaches to ameliorate the impact of IVDD.