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.
Highlights
Spinal cord injury (SCI) is one of the most severe types of neurological damage and often results in permanent dysfunction of movement and sensation, severely affecting quality of life (Friedli et al, 2015; Kjell and Olson, 2016; Tica and Didangelos, 2018)
The complexity of the pathophysiological processes resulting from SCI makes the development of effective therapies very challenging, because the extensive temporal changes in gene expression involved in the secondary phase of SCI are induced by vascular, cellular, and biochemical events (Liu et al, 2009; Yu and Gu, 2019)
As important regulators of gene expression and molecular networks, the use of non-coding RNAs may serve as an innovative therapeutic strategy for treating SCI (Yu et al, 2015). ncRNAs are categorized into many different types, including small nuclear RNAs, small nucleolar RNAs, transfer RNAs, ribosomal RNAs, PIWI (P-element-induced wimpy testis)-interacting RNAs, miRNAs, long ncRNAs, and circRNAs
Summary
Spinal cord injury (SCI) is one of the most severe types of neurological damage and often results in permanent dysfunction of movement and sensation, severely affecting quality of life (Friedli et al, 2015; Kjell and Olson, 2016; Tica and Didangelos, 2018). The nervous system is a delicate system, orchestrated by numerous genes, and SCI strongly impairs such a coordinated environment (Hara et al, 2017). In contrast to linear RNAs (messenger RNAs [mRNAs]), microRNAs (miRNAs), which are characterized by 5 cap and 3 tail structures, circRNAs are characterized by a covalently closed-loop structure that is generated by back-splicing (Bagchi, 2018). An increasing number of studies support the notion that circRNAs orchestrate gene expression by acting as miRNA sponges, interacting with RNA binding proteins, modulating transcription, and affecting numerous diseases, including cancer, as well as cardiovascular and neurological diseases (Floris et al, 2017; Ji et al, 2018; Li et al, 2018; Zhong et al, 2018)
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