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Differential Circular RNA Expression Profiles Following Spinal Cord Injury in Rats: A Temporal and Experimental Analysis.

ABSTRACT: Spinal cord injury (SCI), one of the most severe types of neurological damage, results in persistent motor and sensory dysfunction and involves complex gene alterations. Circular RNAs (circRNAs) are a recently discovered class of regulatory molecules, and their roles in SCI still need to be addressed. This study comprehensively investigated circRNA alterations in rats across a set time course (days 0, 1, 3, 7, 14, 21, and 28) after hemisection SCI at the right T9 site. A total of 360 differentially expressed circRNAs were identified using RNA sequencing. From these, the functions of the exonic circRNA_01477 were further explored in cultured spinal cord astrocytes. Knockdown of circRNA_01477 significantly inhibited astrocyte proliferation and migration. The circRNA_01477/microRNAs (miRNA)/messenger RNA (mRNA) interaction network was visualized following microarray assay. Among the downregulated differentially expressed mRNAs, four of the seven validated genes were controlled by miRNA-423-5p. We then demonstrated that miRNA-423-5p is significantly upregulated after circRNA_01477 depletion. In summary, this study provides, for the first time, a systematic evaluation of circRNA alterations following SCI and an insight into the transcriptional regulation of the genes involved. It further reveals that circRNA_01477/miR-423-5p could be a key regulator involved in regulating the changeable regeneration environment that occurs during recovery from SCI.

SUBMITTER: Wu R

PROVIDER: S-EPMC6916439 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Differential Circular RNA Expression Profiles Following Spinal Cord Injury in Rats: A Temporal and Experimental Analysis.

Wu Ronghua R Mao Susu S Wang Yaxian Y Zhou Shuoshuo S Liu Yan Y Liu Mei M Gu Xiaosong X Yu Bin B

Frontiers in neuroscience 20191210

Spinal cord injury (SCI), one of the most severe types of neurological damage, results in persistent motor and sensory dysfunction and involves complex gene alterations. Circular RNAs (circRNAs) are a recently discovered class of regulatory molecules, and their roles in SCI still need to be addressed. This study comprehensively investigated circRNA alterations in rats across a set time course (days 0, 1, 3, 7, 14, 21, and 28) after hemisection SCI at the right T9 site. A total of 360 differentia ...[more]

PMID: 31920480

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Project description:BackgroundNeurogenic bladder (NB) following suprasacral spinal cord injury (SSCI) is an interstitial disease with the structural remodeling of bladder tissue and matrix over-deposition. Circular RNAs (circRNAs) are involved in fibrotic disease development through their post-transcriptional regulatory functions. This study aimed to use transcriptome high-throughput sequencing to investigate the process of NB and bladder fibrosis after SSCI.MethodsSpinal cord transection at the T10-T11 level was used to construct the SSCI model in rats (10-week-old female Wistar rats, weighing 200 ± 20 g). The bladders were collected without (sham group) and with (SSCI 1-3 groups) NB status. Morphological examination was conducted to assess the extent of bladder fibrosis. Additionally, RNA sequencing was utilized to determine mRNAs and circRNAs expression patterns. The dynamic changes of differentially expressed mRNAs (DEMs) and circRNAs (DECs) in different periods of SSCI were further analyzed.ResultsBladder weight, smooth muscle cell hypertrophy, and extracellular matrix gradually increased after SSCI. Compared with the sham group, 3,255 DEMs and 1,339 DECs, 3,449 DEMs and 1,324 DECs, 884 DEMs, and 1,151 DECs were detected in the SSCI 1-3 groups, respectively. Specifically, circRNA3621, circRNA0617, circRNA0586, and circRNA4426 were significant DECs common to SSCI 1-3 groups compared with the sham group. Moreover, Gene Ontology (GO) enrichment suggested that inflammatory and chronic inflammatory responses were the key events in NB progression following SSCI. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment associated with the "Chemokine signaling pathway", the "IL-17 signaling pathway", and the "TGF-beta signaling pathway" suggests their potential involvement in regulating biological processes. The circRNA-miRNA-mRNA interaction networks of DECs revealed rno-circ-2239 (micu2) as the largest node, indicating that the rno-circ-2239-miRNA-mRNA-mediated network may play a critical role in the pathogenesis of SSCI-induced NB.ConclusionsThis study offers a comprehensive outlook on the possible roles of DEMs and DECs in bladder fibrosis and NB progression following SSCI. These findings have the potential to serve as novel biomarkers and therapeutic targets.

Project description:Spinal cord injury (SCI) is mostly caused by trauma. As primary mechanical injury is unavoidable in SCI, a focus on the pathophysiology and underlying molecular mechanisms of SCI-induced secondary injury is necessary to develop promising treatments for SCI patients. Circular RNAs (circRNAs) are associated with various diseases. Nevertheless, studies to date have not yet determined the functional roles of circRNAs in traumatic SCI. We examined circRNA expression profiles in the contused spinal cords of rats using microarray and quantitative reverse transcription-PCR (qRT-PCR) then predict their potential roles in post-SCI pathophysiology with bioinformatics. We found a total of 1676 differentially expressed circRNAs (fold change ≥ 2.0; P < 0.05) in spinal cord 3 days after contusion using circRNA microarray; 1261 circRNAs were significantly downregulated, whereas the remaining 415 were significantly upregulated. Then, five selected circRNAs, namely, rno_circRNA_005342, rno_circRNA_015513, rno_circRNA_002948, rno_circRNA_006096, and rno_circRNA_013017 were all significantly downregulated in the SCI group after verification by qRT-PCR, demonstrating a similar expression pattern in both microarray and PCR data. The next section of the study was concerned with the prediction of circRNA/miRNA/mRNA interactions using bioinformatics analysis. In the final part of the study, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses indicated carbohydrate metabolic process was one of the most significant enrichments and meaningful terms after GO analysis, and the top two signaling pathways affected by the circRNAs-miRNAs axes were the AMP-activated protein kinase signaling pathway and the peroxisome related pathway. In summary, this study showed an altered circRNA expression pattern that may be involved in physiological and pathological processes in rats after traumatic SCI, providing deep insights into numerous possibilities for SCI treatment targets by regulating circRNAs.

Dataset Information

Differential Circular RNA Expression Profiles Following Spinal Cord Injury in Rats: A Temporal and Experimental Analysis.

Publications

Differential Circular RNA Expression Profiles Following Spinal Cord Injury in Rats: A Temporal and Experimental Analysis.

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