MBD1-dependent recruitment of SUV39h1 induces H3K9me3-mediated transcriptional silencing of <i>Oprm1</i> in dorsal root ganglia after peripheral nerve injury

The downregulation of mu-opioid receptor (MOR) expression in dorsal root ganglia (DRG) following peripheral nerve injury plays a pivotal role in neuropathic pain development and contributes to the reduced efficacy of morphine analgesia. The molecular mechanisms underlying this transcriptional silencing remain poorly understood. In this study, we demonstrate that peripheral nerve injury induces upregulation of methyl-CpG-binding domain protein 1 (MBD1) and histone lysine methyltransferase SUV39H1, leading to increased trimethylation of histone H3 at lysine 9 (H3K9me3) at the <i>Oprm1</i> gene locus in injured DRG neurons. Genetic ablation of MBD1 reversed injury-induced MOR downregulation at both mRNA and protein levels, attenuated H3K9me3 enrichment at the <i>Oprm1</i> promoter, and alleviated neuropathic pain behaviors, despite persistent SUV39H1 upregulation. Mechanistic studies revealed that nerve injury enhances the recruitment of SUV39H1 and H3K9me3 to the <i>Oprm1</i> promoter, which is dependent on MBD1. Our findings establish a novel epigenetic mechanism wherein MBD1-mediated recruitment of SUV39H1 promotes H3K9me3-dependent transcriptional silencing of <i>Oprm1</i> in DRG neurons following peripheral nerve injury.