Possible epigenetic regulatory effect of dysregulated circular RNAs in epilepsy

Abstract

Circular RNAs (circRNAs) involve in the epigenetic regulation and its major mechanism is the sequestration of the target micro RNAs (miRNAs). We hypothesized that circRNAs might be related with the pathophysiology of chronic epilepsy and evaluated the altered cir-cRNA expressions and their possible regulatory effects on their target miRNAs and mRNAs in a mouse epilepsy model. The circRNA expression profile in the hippocampus of the pilocarpine mice was analyzed and compared with control. The correlation between the expression of miRNA binding sites (miRNA response elements, MRE) in the dysregulated circRNAs and the expression of their target miRNAs was evaluated. As miRNAs also inhibit their target mRNAs, circRNA-miRNA-mRNA regulatory network, comprised of dysregulated RNAs that targets one another were searched. For the identified networks, bioinformatics analyses were performed. As the result, Forty-three circRNAs were dysregulated in the hippocampus (up-regulated, 26; down-regulated, 17). The change in the expression of MRE in those circRNAs negatively correlated with the change in the relevant target miRNA expression (r = -0.461, P<0.001), supporting that circRNAs inhibit their target miRNA. 333 dysregulated circRNA-miRNA-mRNA networks were identified. Gene ontology and pathway analyses demonstrated that the up-regulated mRNAs in those networks were closely related to the major processes in epilepsy. Among them, STRING analysis identified 37 key mRNAs with abundant (�4) interactions with other dysregulated target mRNAs. The dysregulation of the circRNAs which had multiple interactions with key mRNAs were validated by PCR. We concluded that dysregulated circRNAs might have a pathophysiologic role in chronic epilepsy by regulating multiple disease relevant mRNAs via circRNA−miRNA −mRNA interactions.

CircRNA Expression Patterns and circRNA-miRNA-mRNA Networks During CV-A16 Infection of SH-SY5Y Cells

“…A large number of reports have shown that circular RNAs affect miRNA-mediated regulation of gene expression through miRNA sequestration [20]. In order to better excavate the circRNAs involved in the pathogenic mechanism of CV-A16 infection, we selected circRNAs related to "Immune system process" in GO-BPs analysis and circRNAs related to "In ammation mediated by chemokine and cytokine signaling pathway" in KEGG analysis.…”

The Secret Garden of Neuronal circRNAs

“…Most studies on circRNA expression in neuronal diseases correlates the circRNA expression profile with miRNA and mRNA profiles ( Table 2 ). Disease-regulatory networks of circRNA-miRNA-mRNA are bioinformatically extracted, by the identification of microRNAs targeting the circRNA sequences with an opposite differential expression, and the miRNA target mRNA with a regulation similar to circRNA [ 81 , 90 , 93 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 ]. Based on the presence of one to seven miRNA target sequences on the circRNA, the decrease in miRNA levels is associated with the observed increase in the cognate circRNA levels through a sponge mechanism, in which circRNAs act as competing endogenous RNAs [ 124 , 125 , 126 , 127 ].…”

Differentially expressed circRNA and functional pathways in the hippocampus of epileptic mice based on next‐generation sequencing

“…Epilepsy is a destructive neurological disease characterized by repeated spontaneous seizures, which have serious health and economic burdens, and greatly reduce the quality of life for those affected. [1][2][3][4] This common chronic neurological disease affects almost 50 million people worldwide. 5 Regardless of the type of primary injury, common pathological reactions occur around the damaged brain tissue during the incubation period, forming an abnormal neural network and resulting in neuronal synchronization overexcitation.…”