Neural Regeneration Research ›› 2021, Vol. 16 ›› Issue (10): 2048-2055.doi: 10.4103/1673-5374.308100

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Role of circular RNA expression in the pathological progression after spinal cord injury

Wen-Zhao Wang#, Jun Li#, Lei Liu, Zheng-Dong Zhang, Ming-Xin Li, Qin Li, Hui-Xu Ma, Hai Yang, Xiao-Ling Hou*   

  1. Department of Orthopedics, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, Sichuan Province, China
  • Online:2021-10-15 Published:2021-03-19
  • Contact: Xiao-Ling Hou, 296825257@qq.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81874002 (to LL); the Science and Technology Support Project of Sichuan Province of China, Nos. 2018SZ0159 (to LL), 2018SZ0246 (to XLH); the Innovation and Entrepreneurship Project of Sichuan Technology Gallery of China, Nos. 2019JDRC0100 (to JL), 2020JDRC0054 (to WZW); the National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, China, Nos. Y2018B22 (to LL), Z20192013 (to JL) and West China Hospital Postdoctoral Research and Development Fund, No. 2019HXBH068 (to JL). 

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Abstract: Differential expression of non-coding RNA after traumatic spinal cord injury (TSCI) is closely related to the pathophysiological process. The purposes of this study were to systematically profile and characterize expression of circular RNA (circRNA) in the lesion epicenter of spinal tissues after TSCI, and predict the structure and potential function of the regulatory circRNA/miRNA network. Forty-eight C57BL/6 mice were randomly and equally assigned to two groups: one subjected to TSCI at T8–10 with an Allen’s drop impactor, and a second subjected to laminectomy without TSCI. Spinal cord samples were stained with hematoxylin and eosin, sequenced, and validated. RNA-Seq, Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, and network analyses (Targetscan and miRanda) were used to predict and annotate the circRNA/miRNA/mRNA network. Luciferase reporter, quantitative reverse transcription polymerase chain reaction, and western blot assays were used to profile expression and regulation patterns of the network in mouse models of TSCI. Hematoxylin-eosin staining revealed severe damage to the blood-spinal cord barrier after TSCI. Differentially expressed circRNA and miRNA profiles were obtained after TSCI; differentially expressed circRNAs, which were abundant in the cytoplasm, were involved in positive regulation of transcription and protein phosphorylation. miR-135b-5p was the most significantly downregulated miRNA after TSCI; circRNAAbca1 and KLF4 were predicted to be its target circRNA and mRNA, respectively. Subsequently, the circAbca1/miR-135b-5P/KLF4 regulatory axis was predicted and constructed, and its targeted binding was verified. After inhibiting circAbca1, GAP43 expression was upregulated. Differential expression of circRNAs might play an important role after TSCI. circAbca1 plays a neuroinhibitory role by targeted binding of the miR-135b-5P/KLF4 axis. The identified circRNA/miRNA/mRNA network could provide the basis for understanding pathophysiological mechanisms underlying TSCI, as well as guide the formulation of related therapeutic strategies. All animal protocols were approved by the Research Ethics Committee of West China Hospital of China (approval No. 2017128) on May 16, 2017. 

Key words: bioinformatics, circRNA/miRNA/mRNA network, circular RNA, gene, KLF4, miR-135b-5p, spinal cord injury, trauma

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