A nerve injury–specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression
Shibin Du, … , Steve Davidson, Yuan-Xiang Tao
Shibin Du, … , Steve Davidson, Yuan-Xiang Tao
Published July 1, 2022
Citation Information: J Clin Invest. 2022;132(13):e153563. https://doi.org/10.1172/JCI153563.
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A nerve injury–specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression

Abstract

Maladaptive changes of nerve injury–associated genes in dorsal root ganglia (DRGs) are critical for neuropathic pain genesis. Emerging evidence supports the role of long noncoding RNAs (lncRNAs) in regulating gene transcription. Here we identified a conserved lncRNA, named nerve injury–specific lncRNA (NIS-lncRNA) for its upregulation in injured DRGs exclusively in response to nerve injury. This upregulation was triggered by nerve injury–induced increase in DRG ELF1, a transcription factor that bound to the NIS-lncRNA promoter. Blocking this upregulation attenuated nerve injury–induced CCL2 increase in injured DRGs and nociceptive hypersensitivity during the development and maintenance periods of neuropathic pain. Mimicking NIS-lncRNA upregulation elevated CCL2 expression, increased CCL2-mediated excitability in DRG neurons, and produced neuropathic pain symptoms. Mechanistically, NIS-lncRNA recruited more binding of the RNA-interacting protein FUS to the Ccl2 promoter and augmented Ccl2 transcription in injured DRGs. Thus, NIS-lncRNA participates in neuropathic pain likely by promoting FUS-triggered DRG Ccl2 expression and may be a potential target in neuropathic pain management.

Authors

Shibin Du, Shaogen Wu, Xiaozhou Feng, Bing Wang, Shangzhou Xia, Lingli Liang, Li Zhang, Gokulapriya Govindarajalu, Alexander Bunk, Feni Kadakia, Qingxiang Mao, Xinying Guo, Hui Zhao, Tolga Berkman, Tong Liu, Hong Li, Jordan Stillman, Alex Bekker, Steve Davidson, Yuan-Xiang Tao

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Figure 1

Identification of NIS-lncRNA in DRGs.

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Identification of NIS-lncRNA in DRGs. (A) NIS-lncRNA transcript (NIS) in...
(A) NIS-lncRNA transcript (NIS) in the lumbar DRGs of naive mouse, rat, and human using reverse transcriptase (RT) PCR with strand-specific primers. GAPDH is a control. Lane C: H2O. M: DNA ladder marker. n = 3 repeats per species. (B) Schematic diagrams of full-length NIS V1 and V2. (C) Northern blot expression analysis of NIS V1 and V2 (arrows) in the ipsilateral L4 DRG on day 7 after SNL. M: RNA marker. n = 3 repeats (10 mice per repeat). (D) NIS V1 and V2 transcripts in different tissues of normal mice. SC, spinal cord; FC, frontal cortex; BS, brainstem; Cere, cerebellum; Hip, hippocampus; NC, no-template control. Tuba-1a is a loading control. n = 3 mice. (E) Relative expression ratios of Gapdh mRNA, Tuba-1a mRNA, H19, Malat1, and NIS V1/V2 in nucleus versus cytoplasm from DRG. n = 5 mice. (F) In vitro translation of NIS V1 and V2 using the Promega Transcend Non-Radioactive Translation Detection Systems. Luciferase and Creb1 are used as controls for coding RNA. n = 3 repeats. (G) Ribosome profiling of NIS-lncRNA and Tuba-1a. The blue rectangles represent their corresponding exons. Signal ratios of ribosome profiling to RNA sequencing (total) for mRNAs (Gapdh and Tuba-1a) and lncRNAs (NIS-lncRNA, H19, and Malat1). RPF, ribosome-protected fragments. n = 3 mice.