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Genome‑wideBrain DNAMethylationandGeneExpression Patterns Unravel Epigenetic Reprogramming in Mesial Temporal Lobe Epilepsy

ABSTRACT: Mesial temporal lobe epilepsy (MTLE) is the most common drug-resistant epilepsy in adults, characterized by hippocampus sclerosis. To date, the etiology of MTLE epileptogenesis and the molecular mechanisms underlying hippocampus sclerosis remain largely unclear. Altered genome-wide DNA methylation patterns and differential gene expression have been reported to be involved in the pathophysiological mechanism of epileptogenesis. To discover epigenetic reprogramming patterns associated with MTLE, we used a higher-throughput microarray, Illumina Infinium 850 K BeadChip, and RNA sequence to analyze epigenome-wide DNA methylation and related gene expressions. We also performed an enrichment analysis to find differences between the patients and autopsy controls. Through data analysis we identified 1832 DNA differentially methylated sites, and ten differentially methylated regions in several chromosomes. The differentially methylated genes were found enriched in "synaptic vesicle", "synaptic vesicle exocytosis", "regulation of synaptic plasticity", "Parkinson's disease", and "Oxidative phosphorylation". Correlation analysis of RNA expression and DNA methylation revealed that 16/48 genes’ DNA methylation marks residing in the promoter region, and 32/48 were located within the gene body. These findings assist with a better understanding of the molecular pathogenesis of MTLE and aid in designing effective tailored interventions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272142 | GEO | 2025/07/31

REPOSITORIES: GEO

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Project description:Morphological changes in mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (mTLE-HS) are well characterized. Yet it remains elusive whether these are a consequence of seizures or originate from a hitherto unknown underlying pathology. We recently published data on changes in gene expression (GE) and DNA methylation (DNAm) in the ipsilateral hippocampus (ILH), using the intracortical kainate mouse model of mTLE-HS. In order to explore the effects of epileptic activity alone and also to further disentangle what triggers morphological alterations, we investigated glial and neuronal changes in GE and DNAm in the contralateral hippocampus (CLH). The intracortical kainic acid mouse model of mTLE-HS was used to elicit status epilepticus. Hippocampi contralateral to injection site from 8 kainate injected (KA) and 8 sham (SH) mice were extracted, and shock frozen at 24 hours post injection. Glial- and neuronal nuclei were sorted by flow cytometry. Alterations in GE and DNAm were assessed using reduced representation bisulfite sequencing (RRBS) and RNA sequencing (RNAseq). The R package edgeR was used for statistical analysis. The CLH featured substantial, mostly cell-specific changes in both GE and DNAm in glia and neurons. While changes in GE overlapped to a great degree between CLH and ILH, alterations in DNAm did not. In the CLH we found a significantly lower number of glial genes up- and downregulated compared to previous results from the ILH. Furthermore, several genes and pathways potentially involved in anti-epileptogenic effects were upregulated in the CLH. By comparing GE data from the CLH to previous results from the ILH (featuring hippocampal sclerosis), we derive potential upstream targets for epileptogenesis, including glial Cox2 and Cxcl10. Despite the absence of morphological changes, the CLH displays substantial changes in GE and DNAm. We find that GE changes related to potential anti-epileptogenic effects seem to dominate compared to pro-epileptogenic effects in the CLH and speculate whether this imbalance contributes to prevent morphological alterations like neuronal death and reactive gliosis.

Project description:Mesial Temporal Lobe Epilepsy (MTLE) is a chronic disease characterized by recurrent unprovoked partial seizures. Current treatments lack long-term efficacy and typically act only to ameliorate the symptomology, rather than to modify the course of the disease. Chronic kainic acid (KA)-induced models of MTLE mimic prominent histopathological and electroencephalographic features of human MTLE, including hippocampal sclerosis, CA1 neuronal loss, astrogliosis, microgliosis, and electrographic hippocampal discharges. Here we examined the transcriptional profiles of the hippocampus of KA - vs sham-injected mice from epileptogenesis to the stabilization of spontaneous recurring seizures. KA (1 nmol) or saline (sham) was injected unilaterally into the dorsal hippocampus of 12 week old C57BL/6J mice, and the ipsilateral (IL) and contralateral (CL) hippocampi were isolated for whole-genome expression profiling (Illumina microarray) or immunohistochemistry 7, 28 and 60 d later. Differential gene expression analysis of the IL hippocampus indicated that 1349, 484, and 439 genes were significantly (fdr<0.05) altered in KA compared to sham at 7, 28 and 60 d, respectively. 108 genes were altered at all time-points assessed, while others were altered in a time-dependent manner, indicative of distinct hippocampal gene expression profiles across the course of disease. Ingenuity Pathway Analysis revealed that specific immune cell and inflammatory signaling pathways were upregulated at 7 and 28 d, in support of a role of neuroinflammation in the disease etiology. The top canonical pathways profile at 60 d was quite distinct from that at 7 and 28 d, although certain inflammatory pathways were still prevalent, indicative of pathways involved in the maintenance of the disease. Consistent with a role of neuroinflammation in MTLE, immunohistochemical analyses demonstrated time-dependent changes in both the intensity of immunoreactivity and number of Iba1- and GFAP-positive cells. To reveal gene networks not apparent with differential expression data alone, weighted gene co-expression analysis (WGCNA) was performed. A gene network that highly associated with 7 d IL-KA (but not 28 and 60 d) was identified, which may point to changes involved in the process of epileptogenesis. Another gene network revealed a group of genes highly associated with changes occurring at 28 and 60 d, but not 7 d, which may point to molecules involved in the generation of spontaneous recurring seizures. Collectively, results indicate that specific pathways, including many associated with neuroinflammation, are activated in a time-dependent manner in MTLE.

Project description:Most patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) have hippocampal sclerosis on the postoperative histopathological examination. Although most patients with MTLE do not refer to a family history of the disease, familial forms of MTLE have been reported. We studied surgical specimens from patients with MTLE who had epilepsy surgery for medically intractable seizures. We assessed and compared messenger RNA (mRNA) expression profiles of the tissue lesion found in patients with familial MTLE (n = 3) and sporadic MTLE (n = 5). In addition, we used data from control hippocampi obtained from a public database (n = 7). We obtained expression profiles using the Human Genome U133 Plus 2.0 (Affymetrix) microarray platform. Overall, the molecular profile identified in familial MTLE was distinct from that found in sporadic MTLE. In the tissue of patients with familial MTLE, we found an over-representation of the biological pathways related to protein response, mRNA processing, and synaptic plasticity and function. In sporadic MTLE, the gene expression profile suggests that the inflammatory response is highly activated. We also found enrichment of gene sets involved in inflammatory cytokines and mediators and chemokine receptor pathways in both groups. However, in sporadic MTLE, we also found enrichment of epidermal growth factor signaling, prostaglandin synthesis and regulation, and microglia pathogen phagocytosis pathways. Furthermore, based on the gene expression signatures, we identified different potential compounds to treat patients with familial and sporadic MTLE. To our knowledge, this is the first study assessing the mRNA profile in surgical tissue obtained from patients with familial MTLE and comparing it with sporadic MTLE. Our results clearly show that, despite phenotypic similarities, both forms of MTLE present distinct molecular signatures, thus suggesting different underlying molecular mechanisms that may require distinct therapeutic approaches.

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Genome‑wideBrain DNAMethylationandGeneExpression Patterns Unravel Epigenetic Reprogramming in Mesial Temporal Lobe Epilepsy

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