TY - JOUR
T1 - Coding and non-coding transcriptome of mesial temporal lobe epilepsy
T2 - Critical role of small non-coding RNAs
AU - Mills, J.D.
AU - van Vliet, E.A.
AU - Chen, B.J.
AU - Janitz, M.
AU - Anink, J.J.
AU - Baayen, J.C.
AU - Idema, S.
AU - Devore, S.
AU - Friedman, D.
AU - Diehl, B.
AU - Thom, M.
AU - Scott, C.
AU - Thijs, R.
AU - Aronica, E.
AU - Devinsky, O.
N1 - With supplementary files
PY - 2020/2
Y1 - 2020/2
N2 - 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.
AB - 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.
KW - Epilepsy
KW - Mesial temporal lobe epilepsy
KW - Non-coding RNA
KW - Transcriptomics
KW - microRNA
UR - https://pure.uva.nl/ws/files/48021042/1_s2.0_S0969996119302876_mmc1.xlsx
UR - https://pure.uva.nl/ws/files/48021044/1_s2.0_S0969996119302876_mmc2.docx
UR - https://pure.uva.nl/ws/files/48021046/1_s2.0_S0969996119302876_mmc3.docx
UR - https://pure.uva.nl/ws/files/48021048/1_s2.0_S0969996119302876_mmc4.pdf
UR - http://www.scopus.com/inward/record.url?scp=85074197934&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.nbd.2019.104612
DO - https://doi.org/10.1016/j.nbd.2019.104612
M3 - Article
C2 - 31533065
SN - 0969-9961
VL - 134
JO - Neurobiology of Disease
JF - Neurobiology of Disease
M1 - 104612
ER -