Transcriptome analysis reveals higher levels of mobile element-associated abnormal gene transcripts in temporal lobe epilepsy patients

Abstract

ObjectiveTo determine role of abnormal splice variants associated with mobile elements in epilepsy. MethodsPublicly available human RNA-seq-based transcriptome data for laser-captured dentate granule cells of post-mortem hippocampal tissues from temporal lobe epilepsy patients with (TLE, N=14 for 7 subjects) and without hippocampal sclerosis (TLE-HS, N=8 for 5 subjects) and healthy individuals (N=51), surgically resected bulk neocortex tissues from TLE patients (TLE-NC, N=17). For each individual sample, de novo transcriptome assembly was performed followed by identification of spliced gene transcripts containing mobile element (ME) sequences (ME-transcripts) to compare the ME-transcript frequency across the sample groups. Enrichment analysis for genes associated with ME-transcripts and detailed sequence examination for representative epileptic genes were performed to analyze the pattern and mechanism of ME-transcripts on gene function. ResultsWe observed significantly higher levels of ME-transcripts in the hippocampal tissues of epileptic patients, particularly in TLE-HS. Among ME classes, SINEs were shown to be the most frequent contributor to ME-transcripts followed by LINEs and DNA transposons. These ME sequences almost in all cases represent older MEs normally located in the intron sequences, leading abnormal splicing variants. For protein coding genes, ME sequences were mostly found in the 3-UTR regions, with a significant portion also in the coding sequences (CDS) leading to reading frame disruption. Genes associated with ME-transcripts showed enrichment for involvement in the mRNA splicing process in all sample groups, with bias towards neural and epilepsy-associated genes in the epileptic transcriptomes. SignificanceOur data suggest that abnormal splicing involving MEs, leading to loss of function in critical genes, plays a role in epilepsy, particularly in TLE-HS, providing a novel insight on the molecular mechanisms underlying epileptogenesis. Key points boxO_LISignificantly higher rates of abnormal splicing variants involving mobile elements (MEs) were observed in the hippocampal tissues of epilepsy patients. C_LIO_LISINEs/Alus are most frequently observed in ME-transcripts followed by LINEs and DNA transposons. C_LIO_LIFor protein coding genes, MEs mostly locate in 3 UTR, but also in coding regions, causing open reading frame disruption, with a bias for neural and epileptic genes. C_LIO_LIAbnormal splicing involving MEs may be a contributing factor in epileptogenesis. C_LI