Downregulation of a Dorsal Root Ganglion‐Specifically Enriched Long Noncoding RNA is Required for Neuropathic Pain by Negatively Regulating RALY‐Triggered Ehmt2 Expression

Nerve injury‐induced maladaptive changes of gene expression in dorsal root ganglion (DRG) neurons contribute to neuropathic pain. Long non‐coding RNAs (lncRNAs) are emerging as key regulators of gene expression. Here, a conserved lncRNA is reported, named DRG‐specifically enriched lncRNA (DS‐lncRNA) for its high expression in DRG neurons. Peripheral nerve injury downregulates DS‐lncRNA in injured DRG due, in part, to silencing of POU domain, class 4, transcription factor 3, a transcription factor that interacts with the DS‐lncRNA gene promoter. Rescuing DS‐lncRNA downregulation blocks nerve injury‐induced increases in the transcriptional cofactor RALY‐triggered DRG Ehmt2 mRNA and its encoding G9a protein, reverses the G9a‐controlled downregulation of opioid receptors and Kcna2 in injured DRG, and attenuates nerve injury‐induced pain hypersensitivities in male mice. Conversely, DS‐lncRNA downregulation increases RALY‐triggered Ehmt2/G9a expression and correspondingly decreases opioid receptor and Kcna2 expression in DRG, leading to neuropathic pain symptoms in male mice in the absence of nerve injury. Mechanistically, downregulated DS‐lncRNA promotes more binding of increased RALY to RNA polymerase II and the Ehmt2 gene promoter and enhances Ehmt2 transcription in injured DRG. Thus, downregulation of DS‐lncRNA likely contributes to neuropathic pain by negatively regulating the expression of RALY‐triggered Ehmt2/G9a, a key neuropathic pain player, in DRG neurons. This work reports that nerve trauma‐induced the downregulation of a dorsal root ganglion‐specifically enriched long noncoding RNA (DS‐lncRNA) promotes the binding of the transcription co‐factor RALY to RNA polymerase II (RNP II) and the Ehmt2 gene promoter, increases the expression of Ehmt2 mRNA and G9a protein, downregulates many pain‐associated genes including Oprm1 mRNA and mu opioid receptor (MOR), and causes neuropathic pain.