Coding and non-coding transcriptome of mesial temporal lobe epilepsy: Critical role of small non-coding RNAs

• Published in: Neurobiology of disease 2020-02, Vol.134, p.104612-104612, Article 104612
• Main Authors: Mills, James D., van Vliet, Erwin A., Chen, Bei Jun, Janitz, Michael, Anink, Jasper J., Baayen, Johannes C., Idema, Sander, Devore, Sasha, Friedman, Daniel, Diehl, Beate, Thom, Maria, Scott, Catherine, Thijs, Roland, Aronica, Eleonora, Devinsky, Orrin
• Format: Article
• Language: English
• Subjects: Adult; Aged; Epilepsy; Epilepsy, Temporal Lobe - genetics; Female; Gene Expression Profiling; Humans; Male; Mesial temporal lobe epilepsy; microRNA; Middle Aged; Non-coding RNA; RNA, Small Untranslated - genetics; Transcriptome; Transcriptomics; Young Adult
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2019.104612

Our understanding of mesial temporal lobe epilepsy (MTLE), one of the most common form of drug-resistant epilepsy in humans, is derived mainly from clinical, imaging, and physiological data from humans and animal models. High-throughput gene expression studies of human MTLE have the potential to uncover molecular changes underlying disease pathogenesis along with novel therapeutic targets. Using RNA- and small RNA-sequencing in parrallel, we explored differentially expressed genes in the hippocampus and cortex of MTLE patients who had undergone surgical resection and non-epileptic controls. We identified differentially expressed genes in the hippocampus of MTLE patients and differentially expressed small RNAs across both the cortex and hippocampus. We found significant enrichment for astrocytic and microglial genes among up-regulated genes, and down regulation of neuron specific genes in the hippocampus of MTLE patients. The transcriptome profile of the small RNAs reflected disease state more robustly than mRNAs, even across brain regions which show very little pathology. While mRNAs segregated predominately by brain region for MTLE and controls, small RNAs segregated by disease state. In particular, our data suggest that specific miRNAs (e.g., let-7b-3p and let-7c-3p) may be key regulators of multiple pathways related to MTLE pathology. Further, we report a strong association of other small RNA species with MTLE pathology. As such we have uncovered novel elements that may contribute to the establishment and progression of MTLE pathogenesis and that could be leveraged as therapeutic targets. •At the molecular level MTLE is characterized by gene expression changes in the hippocampus.•Up-regulation of glia genes and down-regulation of neuronal genes was seen in the hippocampus.•small RNAs reflect disease state more robustly then mRNAs.•let-7b-3p and let-7c-3p maybe be key regulators of multiple pathways involved in MTLE pathology.