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DHX9/DNA-tandem repeat-dependent downregulation of ciRNA-Fmn1 in the dorsal horn is required for neuropathic pain

Acta Pharmacologica Sinica volume 44, pages 1748–1767 (2023)Cite this article

Abstract

Circular RNAs (ciRNAs) are emerging as new players in the regulation of gene expression. However, how ciRNAs are involved in neuropathic pain is poorly understood. Here, we identify the nervous-tissue-specific ciRNA-Fmn1 and report that changes in ciRNA-Fmn1 expression in spinal cord dorsal horn neurons play a key role in neuropathic pain after nerve injury. ciRNA-Fmn1 was significantly downregulated in ipsilateral dorsal horn neurons after peripheral nerve injury, at least in part because of a decrease in DNA helicase 9 (DHX9), which regulates production of ciRNA-Fmn1 by binding to DNA-tandem repeats. Blocking ciRNA-Fmn1 downregulation reversed nerve-injury-induced reductions in both the binding of ciRNA-Fmn1 to the ubiquitin ligase UBR5 and the level of ubiquitination of albumin (ALB), thereby abrogating the nerve-injury-induced increase of ALB expression in the dorsal horn and attenuating the associated pain hypersensitivities. Conversely, mimicking downregulation of ciRNA-Fmn1 in naïve mice reduced the UBR5-controlled ubiquitination of ALB, leading to increased expression of ALB in the dorsal horn and induction of neuropathic-pain-like behaviors in naïve mice. Thus, ciRNA-Fmn1 downregulation caused by changes in binding of DHX9 to DNA-tandem repeats contributes to the genesis of neuropathic pain by negatively modulating UBR5-controlled ALB expression in the dorsal horn.

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Fig. 1: Identification of nervous-tissue-enriched ciRNA-Fmn1 in dorsal horn neurons in the spinal cord.
Fig. 2: Identification of ciRNA-Fmn1 and its cellular distribution in the spinal cord.
Fig. 3: Downregulation of ciRNA-Fmn1 in the dorsal horn after nerve injury.
Fig. 4: ciRNA-Fmn1 contributes to the initiation and maintenance of neuropathic pain.
Fig. 5: DHX9 downregulation reduces ciRNA-Fmn1 expression in a DNA-tandem repeats-dependent manner in the dorsal horn.
Fig. 6: DHX9 controls the downregulation of dorsal horn ciRNA-Fmn1 and is required for neuropathic pain.
Fig. 7: ciRNA-Fmn1 negatively regulates the expression of ALB in the dorsal horn after peripheral nerve injury.
Fig. 8: ciRNA-Fmn1-triggered reduction of spinal ALB contributes to neuropathic pain.
Fig. 9: ciRNA-Fmn1 downregulation attenuates UBR5-controlled ALB degeneration in the dorsal horn after CCI.
Fig. 10: Schematic of the proposed pathways: DHX9 control of ciRNA-Fmn1 downregulation in a DNA-tandem repeats-dependent manner contributes to neuropathic pain by negatively regulating UBR5-triggered ALB levels in dorsal horn neurons.

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Acknowledgements

The work was supported by grants from the National Natural Science Foundation of China (82171234, 81971041, 81671096 to ZQP; 82171233 to HJW; 82201391 to QHW; 32200818 to LY; 81901132 to ZYX); Jiang Su-Specially Appointed Professor Project, Natural Science Foundation of Jiangsu Province (BK20201460), and Key project of the Natural Science Foundation of Jiangsu Education Department (22KJA320008), and Key Project of Shanghai Chongming District (CKY2019-1).

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  1. These authors contributed equally: Xiao-dan Liu, Tong Jin, Yang Tao.

Authors and Affiliations

  1. Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China

    Xiao-dan Liu, Yang Tao, Ming Zhang, Qiao-qiao Liu, Ke-hui Yang, Ru-na Wei, Si-yuan Li, Yue Huang, Ling-yun Hao, Qi-hui Wang, Li Yang, Hong-jun Wang, Jun-li Cao & Zhi-qiang Pan

  2. Department of Anesthesiology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, 511518, China

    Xiao-dan Liu

  3. Department of Pain, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, 200072, China

    Tong Jin, Hong-li Zheng & Fu-qing Lin

  4. Department of Anesthesiology, Yancheng Affiliated Hospital of Xuzhou Medical University, Yancheng, 224001, China

    Zhou-ya Xue

  5. Department of Pain, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, China

    Wen Shen

  6. Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA

    Yuan-xiang Tao

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Contributions

ZQP, conceived the project. ZQP and JLC supervised all experiments. XDL, YT, TJ, HLZ, MZ, and LYH performed the experiments; XDL, YT, SYL, YH, QQL, KHY, RNW, HLZ, MZ, QHW, LY, HJW, FQL, WS and ZQP analyzed data; XDL, HJW, and ZQP wrote the draft of paper. YXT discussed the results and edited the paper.

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Correspondence to Hong-jun Wang, Jun-li Cao or Zhi-qiang Pan.

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Liu, Xd., Jin, T., Tao, Y. et al. DHX9/DNA-tandem repeat-dependent downregulation of ciRNA-Fmn1 in the dorsal horn is required for neuropathic pain. Acta Pharmacol Sin 44, 1748–1767 (2023). https://doi.org/10.1038/s41401-023-01082-x

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