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Papers of the Week

Papers: 7 Oct 2023 - 13 Oct 2023

2023 Oct 05

J Neurosci


Editor's Pick

Spinal-specific super enhancer in neuropathic pain.


Tao Y, Wang QH, Li XT, Sun RH, Xu HJ, Liu Y, Zhang M, Li SY, Yang L, Wang HJ, Hao LY, Cao JL, Pan Z


Dysfunctional gene expression in nociceptive pathways plays a critical role in the development and maintenance of neuropathic pain. Super enhancers (SEs), composed of a large cluster of transcriptional enhancers, are emerging as new players in the regulation of gene expression. However, whether SEs participate in nociceptive responses remains unknown. Here, we report a spinal-specific SE (SS-SE) that regulates chronic constriction injury (CCI)-induced neuropathic pain by driving and transcription in dorsal horn neurons. Peripheral nerve injury significantly enhanced the activity of SS-SE and increased the expression of NTMT1 and PRRX2 in the dorsal horn of male mice in a BRD4-dependent manner. Both intrathecal administration of a pharmacological BRD4 inhibitor, JQ1, and CRISPR-Cas9-mediated SE deletion abolished the increased NTMT1 and PRRX2 in CCI mice and attenuated their nociceptive hypersensitivities. Furthermore, knocking down or with siRNA suppressed the injury-induced elevation of p-ERK and GFAP expression in the dorsal horn and alleviated neuropathic pain behaviors. Mimicking the increase in spinal or in naïve mice increased p-ERK and GFAP expression and led to the genesis of neuropathic pain-like behavior. These results redefine our understanding of the regulation of pain-related genes and demonstrate that BRD4-driven increases in SS-SE activity is responsible for the genesis of neuropathic pain through the governance of NTMT1 and PRRX2 expression in dorsal horn neurons. Our findings highlight the therapeutic potential of BRD4 inhibitors for the treatment of neuropathic pain.Super enhancers (SEs) drive gene expression by recruiting master transcription factors, cofactors, and RNA polymerase, but their role in the development of neuropathic pain remains unknown. Here, we report that the activity of a spinal-specific super enhancer (SS-SE), located upstream of the genes and , was elevated in the dorsal horn of mice with neuropathic pain. SS-SE contributes to the genesis of neuropathic pain by driving expression of and Both inhibition of SS-SE with a pharmacological BRD4 inhibitor and genetic deletion of SS-SE attenuated pain hypersensitivities. This study suggests an effective and novel therapeutic strategy for neuropathic pain.