Identification of Specific Circular RNA Expression Patterns and MicroRNA Interaction Networks in Mesial Temporal Lobe Epilepsy

Abstract

Circular RNAs (circRNAs) regulate mRNA translation by binding to microRNAs (miRNAs), and their expression is altered in diverse disorders, including cancer, cardiovascular disease, and Parkinson's disease. Here, we compare circRNA expression patterns in the temporal cortex and hippocampus of patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) and healthy controls. Nine circRNAs showed significant differential expression, including circRNA-HOMER1, which is expressed in synapses. Further, we identified miRNA binding sites within the sequences of differentially expressed (DE) circRNAs; expression levels of mRNAs correlated with changes in complementary miRNAs. Gene set enrichment analysis of mRNA targets revealed functions in heterocyclic compound binding, regulation of transcription, and signal transduction, which maintain the structure and function of hippocampal neurons. The circRNA-miRNA-mRNA interaction networks illuminate the molecular changes in MTLE, which may be pathogenic or an effect of the disease or treatments and suggests that DE circRNAs and associated miRNAs may be novel therapeutic targets.

Enrichment of Circular RNA Expression Deregulation at the Transition to Recurrent Spontaneous Seizures in Experimental Temporal Lobe Epilepsy

“…We validated the upregulation of circ_Arhgap4 and circ_Nav3 at the DOFS and found similar regulation of their circular and linear host transcripts. This is in contrast with earlier findings, in which no obvious correlation was observed between specific circRNAs and the expression of their parental genes in mTLE ( Gray et al, 2020 ). A positive correlation in the expression of circRNA and mRNA species suggests that the RNA changes are a consequence of transcriptional activation of these genes rather than an alteration of splicing events that lead to circRNA formation ( Jeck and Sharpless, 2014 ).…”

“…Over the past years, a plethora of studies has shown that ncRNAs can influence various processes in the nervous system, including neuronal development, apoptosis, neurogenesis, oxidative stress, synaptic plasticity, and immune system activation, that are disturbed in the pathological process leading to mTLE ( Henshall and Kobow, 2015 ; Henshall et al, 2016 ; Shao and Chen, 2017 ; Villa et al, 2019 ; Mills et al, 2020 ). In addition, experimental evidence highlights defects in post-transcriptional regulation in mTLE and the expression and function of different classes of ncRNAs is perturbed in experimental TLE and in TLE patients ( Van Gassen et al, 2008 ; Jimenez-Mateos et al, 2012 ; Kan et al, 2012 ; Gong et al, 2018 ; Lee et al, 2018 ; Li J. et al, 2018 ; Guelfi et al, 2019 ; Fu et al, 2020 ; Gray et al, 2020 ; Venø et al, 2020 ). Together, these observations support the idea that ncRNAs may participate in the process of epileptogenesis.…”

Expression of Circ_Satb1 Is Decreased in Mesial Temporal Lobe Epilepsy and Regulates Dendritic Spine Morphology

“…However, independent expression regulation has also been observed ( Jeck et al, 2013 ; Salzman et al, 2013 ; Ashwal-Fluss et al, 2014 ; Rybak-Wolf et al, 2014 ; Xu et al, 2018 ). Our findings are in line with previous work showing no clear correlation between a set of mTLE-associated circRNAs and linear transcripts from the same loci ( Gray et al, 2020 ). These observations suggest that changes in for example back-splicing rather than transcriptional activation of the SATB1 locus may cause altered circ_Satb1 expression in the hippocampus of mTLE patients.…”

“…Unfortunately, their specific neuronal functions remain poorly understood. Our own work and that of others shows deregulated expression of circRNAs in mTLE patients and in experimental models of epilepsy (e.g., Gong et al, 2018 ; Lee et al, 2018 ; Li et al, 2018 ; Gray et al, 2020 ; Gomes-Duarte et al, 2021 ). For example, we have recently reported enrichment of circRNA deregulation at the transition to recurrent spontaneous seizures ( Gomes-Duarte et al, 2021 ).…”

“…A growing body of experimental evidence implicates non-coding RNAs (ncRNAs) in epilepsy. NcRNAs are deregulated in both human and experimental epilepsy, and have been linked to disease-associated changes in processes such as inflammatory and immune responses, apoptosis, neurogenesis, and neural plasticity ( Henshall and Kobow, 2015 ; Henshall et al, 2016 ; Shao and Chen, 2017 ; Villa et al, 2019 ; Gray et al, 2020 ). Circular RNAs (circRNAs) are a class of long ncRNAs that form a closed-loop structure, in which the 5′ and 3′ splice sites of a pre-mRNA are covalently bound ( Jeck et al, 2013 ; Memczak et al, 2013 ).…”