Identification of potential traumatic spinal cord injury related circular RNA-microRNA networks by sequence analysis_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

WANG Wenzhao ¹ , WANG Shanxi ¹ , ZHANG Zhengdong ^1,2 , LI Jun ¹ , XIE Wei ³ , SU Yanlin ⁴ , CHEN Jianan ⁴ ,  LIU Lei ¹

1. Department of Orthopedics, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China;
2. Department of Orthopedics, the Second People’s Hospital of Jiulongpo District, Chongqing, 400050, P.R.China;
3. Department Emergency Medicine, the Second Affiliated Hospital of Shandong First Medical University, Taian Shandong, 271000, P.R.China;
4. Department of Orthopedics, Jinan Central Hospital Affiliated to Shandong University, Jinan Shandong, 250000, P.R.China;

Corresponding author：

LIU Lei, Email: liuinsistence@163.com

Keywords：

Traumatic spinal cord injury; circular RNA; microRNA; regulatory network

DOI：

10.7507/1002-1892.201905079

Video：

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Objective To systematically profile and characterize the circular RNA (circRNA) and microRNA (miRNA) expression pattern in the lesion epicenter of spinal tissues after traumatic spinal cord injury (TSCI) and predict the structure and potential functions of the regulatory network.Methods Forty-eight adult male C57BL/6 mice (weighing, 18-22 g) were randomly divided into the TSCI (n=24) and sham (n=24) groups. Mice in the TSCI group underwent T_8-10 vertebral laminectomy and Allen’s weight-drop spinal cord injury. Mice in the sham group underwent the same laminectomy without TSCI. The spinal tissues were harvested after 3 days. Some tissues were stained with HE staining to observe the structure. The others were used for sequencing. The RNA-Seq, gene ontology (GO) analysis, and circRNA-miRNA network analyses (TargetScan and miRanda) were used to profile the expression and regulation patterns of network of mice models after TSCI.Results HE staining showed the severe damage to the spinal cord in TSCI group compared with sham group. A total of 17 440 circRNAs and 1 228 miRNAs were identified. The host gene of significant differentially expressed circRNA enriched in the cytoplasm, associated with positive regulation of transcription and protein phosphorylation. mmu-miR-21-5p was the most significant differentially expressed miRNA after TSCI, and circRNA6730 was predicted to be its targeted circRNA. Then a potential regulatory circRNA-miRNA network was constructed.Conclusion The significant differentially expressed circRNAs and miRNAs may play important roles after TSCI. A targeted interaction network with mmu-miR-21-5p at the core of circRNA6730 could provide basis of pathophysiological mechanism, as well as help guide therapeutic strategies for TSCI.

Citation： WANG Wenzhao, WANG Shanxi, ZHANG Zhengdong, LI Jun, XIE Wei, SU Yanlin, CHEN Jianan, LIU Lei. Identification of potential traumatic spinal cord injury related circular RNA-microRNA networks by sequence analysis. Chinese Journal of Reparative and Reconstructive Surgery, 2020, 34(2): 213-219. doi: 10.7507/1002-1892.201905079 Copy

1.	Fouad K, Krajacic A, Tetzlaff W. Spinal cord injury and plasticity: opportunities and challenges. Brain Res Bull, 2011, 84(4-5): 337-342.
2.	Holmes D. Spinal-cord injury: spurring regrowth. Nature, 2017, 552(7684): S49.
3.	Tran AP, Warren PM, Silver J. The biology of regeneration failure and success after spinal cord injury. Physiol Rev, 2018, 98(2): 881-917.
4.	Geng Y, Jiang J, Wu C. Function and clinical significance of circRNAs in solid tumors. J Hematol Oncol, 2018, 11(1): 98.
5.	Kleaveland B, Shi CY, Stefano J, et al. A network of noncoding regulatory RNAs acts in the mammalian brain. Cell, 2018, 174(2): 350-362.
6.	Wang W, Liu R, Su Y, et al. MicroRNA-21-5p mediates TGF-β-regulated fibrogenic activation of spinal fibroblasts and the formation of fibrotic scars after spinal cord injury. Int J Biol Sci, 2018, 14(2): 178-188.
7.	Liu R, Wang W, Wang S, et al. microRNA-21 regulates astrocytic reaction post-acute phase of spinal cord injury through modulating TGF-βsignaling. Aging (Albany NY), 2018, 10(6): 1474-1488.
8.	Wang W, Tang S, Li H, et al. MicroRNA-21a-5p promotes fibrosis in spinal fibroblasts after mechanical trauma. Exp Cell Res, 2018, 370(1): 24-30.
9.	Cristante AF, Barros Filho TE, Marcon RM, et al. Therapeutic approaches for spinal cord injury. Clinics (Sao Paulo), 2012, 67(10): 1219-1224.
10.	Schwab JM, Maas AIR, Hsieh JTC, et al. Raising awareness for spinal cord injury research. Lancet Neurol, 2018, 17(7): 581-582.
11.	Ning B, Gao L, Liu RH, et al. microRNAs in spinal cord injury: potential roles and therapeutic implications. Int J Biol Sci, 2014, 10(9): 997-1006.
12.	Djebali S, Davis CA, Merkel A, et al. Landscape of transcription in human cells. Nature, 2012, 489(7414): 101-108.
13.	Qu S, Yang X, Li X, et al. Circular RNA: A new star of noncoding RNAs. Cancer Lett, 2015, 365(2): 141-148.
14.	Ameres SL, Zamore PD. Diversifying microRNA sequence and function. Nat Rev Mol Cell Biol, 2013, 14(8): 475-488.
15.	Stoicea N, Du A, Lakis DC, et al. The miRNA journey from theory to practice as a CNS biomarker. Front Genet, 2016, 7: 11.
16.	Salzman J, Chen RE, Olsen MN, et al. Cell-type specific features of circular RNA expression. PLoS Genet, 2013, 9(9): e1003777.
17.	You X, Vlatkovic I, Babic A, et al. Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. Nat Neurosci, 2015, 18(4): 603-610.
18.	Venø MT, Hansen TB, Venø ST, et al. Spatio-temporal regulation of circular RNA expression during porcine embryonic brain development. Genome Biol, 2015, 16: 245.
19.	Zhang Z, Yang T, Xiao J. Circular RNAs: promising biomarkers for human diseases. EBioMedicine, 2018, 34: 267-274.
20.	Li TR, Jia YJ, Wang Q, et al. Circular RNA: a new star in neurological diseases. Int J Neurosci, 2017, 127(8): 726-734.
21.	Hara M, Kobayakawa K, Ohkawa Y, et al. Interaction of reactive astrocytes with typeⅠcollagen induces astrocytic scar formation through the integrin-N-cadherin pathway after spinal cord injury. Nat Med, 2017, 23(7): 818-828.
22.	Catenaccio A, Llavero Hurtado M, Diaz P, et al. Molecular analysis of axonal-intrinsic and glial-associated co-regulation of axon degeneration. Cell Death Dis, 2017, 8(11): e3166.

1. Fouad K, Krajacic A, Tetzlaff W. Spinal cord injury and plasticity: opportunities and challenges. Brain Res Bull, 2011, 84(4-5): 337-342.
2. Holmes D. Spinal-cord injury: spurring regrowth. Nature, 2017, 552(7684): S49.
3. Tran AP, Warren PM, Silver J. The biology of regeneration failure and success after spinal cord injury. Physiol Rev, 2018, 98(2): 881-917.
4. Geng Y, Jiang J, Wu C. Function and clinical significance of circRNAs in solid tumors. J Hematol Oncol, 2018, 11(1): 98.
5. Kleaveland B, Shi CY, Stefano J, et al. A network of noncoding regulatory RNAs acts in the mammalian brain. Cell, 2018, 174(2): 350-362.
6. Wang W, Liu R, Su Y, et al. MicroRNA-21-5p mediates TGF-β-regulated fibrogenic activation of spinal fibroblasts and the formation of fibrotic scars after spinal cord injury. Int J Biol Sci, 2018, 14(2): 178-188.
7. Liu R, Wang W, Wang S, et al. microRNA-21 regulates astrocytic reaction post-acute phase of spinal cord injury through modulating TGF-βsignaling. Aging (Albany NY), 2018, 10(6): 1474-1488.
8. Wang W, Tang S, Li H, et al. MicroRNA-21a-5p promotes fibrosis in spinal fibroblasts after mechanical trauma. Exp Cell Res, 2018, 370(1): 24-30.
9. Cristante AF, Barros Filho TE, Marcon RM, et al. Therapeutic approaches for spinal cord injury. Clinics (Sao Paulo), 2012, 67(10): 1219-1224.
10. Schwab JM, Maas AIR, Hsieh JTC, et al. Raising awareness for spinal cord injury research. Lancet Neurol, 2018, 17(7): 581-582.
11. Ning B, Gao L, Liu RH, et al. microRNAs in spinal cord injury: potential roles and therapeutic implications. Int J Biol Sci, 2014, 10(9): 997-1006.
12. Djebali S, Davis CA, Merkel A, et al. Landscape of transcription in human cells. Nature, 2012, 489(7414): 101-108.
13. Qu S, Yang X, Li X, et al. Circular RNA: A new star of noncoding RNAs. Cancer Lett, 2015, 365(2): 141-148.
14. Ameres SL, Zamore PD. Diversifying microRNA sequence and function. Nat Rev Mol Cell Biol, 2013, 14(8): 475-488.
15. Stoicea N, Du A, Lakis DC, et al. The miRNA journey from theory to practice as a CNS biomarker. Front Genet, 2016, 7: 11.
16. Salzman J, Chen RE, Olsen MN, et al. Cell-type specific features of circular RNA expression. PLoS Genet, 2013, 9(9): e1003777.
17. You X, Vlatkovic I, Babic A, et al. Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. Nat Neurosci, 2015, 18(4): 603-610.
18. Venø MT, Hansen TB, Venø ST, et al. Spatio-temporal regulation of circular RNA expression during porcine embryonic brain development. Genome Biol, 2015, 16: 245.
19. Zhang Z, Yang T, Xiao J. Circular RNAs: promising biomarkers for human diseases. EBioMedicine, 2018, 34: 267-274.
20. Li TR, Jia YJ, Wang Q, et al. Circular RNA: a new star in neurological diseases. Int J Neurosci, 2017, 127(8): 726-734.
21. Hara M, Kobayakawa K, Ohkawa Y, et al. Interaction of reactive astrocytes with typeⅠcollagen induces astrocytic scar formation through the integrin-N-cadherin pathway after spinal cord injury. Nat Med, 2017, 23(7): 818-828.
22. Catenaccio A, Llavero Hurtado M, Diaz P, et al. Molecular analysis of axonal-intrinsic and glial-associated co-regulation of axon degeneration. Cell Death Dis, 2017, 8(11): e3166.

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Identification of potential traumatic spinal cord injury related circular RNA-microRNA networks by sequence analysis

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