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

Lachlan G Gray,Daniel Friedman,Ashton Curry-Hyde,Orrin Devinsky,Roland D Thijs,Catherine Scott,Michael Janitz,James D Mills,Sasha Devore,Eleonora Aronica,Maria Thom

doi:10.3389/fgene.2020.564301

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.

Highlights

Circular RNAs are a unique class of non-coding RNA found in human tissues and are linked to diverse diseases (Chen et al, 2016, 2018)
Mesial temporal lobe epilepsy (MTLE) is a common human epilepsy and is often accompanied by hippocampal sclerosis (HS; Engel, 2001): a pathology associated with pharmacoresistance (Blümcke et al, 2013)
After merging the circRNAs to find those commonly detected by both tools, 1515 circRNAs were detected across all samples; the quantity of circRNA was expected, as circRNA is highly abundant in the brain (Gokool et al, 2020)

Summary

Introduction

Circular RNAs (circRNAs) are a unique class of non-coding RNA found in human tissues and are linked to diverse diseases (Chen et al, 2016, 2018). CircRNAs originate from backsplicing of the precursor-mRNA (pre-mRNA) transcript. This alternative (back) splicing of pre-mRNA transcripts occurs when the spliceosome covalently joins the 3 end of a downstream exon to the 5 end of an upstream exon. Mesial temporal lobe epilepsy (MTLE) is a common human epilepsy and is often accompanied by hippocampal sclerosis (HS; Engel, 2001): a pathology associated with pharmacoresistance (Blümcke et al, 2013). Pharmacoresistant epilepsy and memory impairment may result from cell loss, synaptic reorganization, altered excitatory–inhibitory balance, and aberrant hippocampal discharges (Scharfman et al, 2003; Blümcke et al, 2009; Gelinas et al, 2016). Many MTLE patients undergo surgical resection if seizures are pharmacoresistant, with seizure-free rates of 60–80%, and reduced seizures in 95%. Many surgical candidates do not undergo epilepsy surgery due to limited health care resources or fears of complications (Kang et al, 2016)

Methods

Results

Conclusion