|Year : 2020 | Volume
| Issue : 2 | Page : 314--315
Epigenetic Regulation in Mesial Temporal Lobe Epilepsy Associated with Hippocampal Sclerosis
Mujeeba Rehman1, Vipul Agarwal1, Kanika Sharma2, Vikas Mishra1,
1 Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India
2 Department of Neurology, The University of Iowa Hospitals and Clinics, Iowa City, United States
Department of Pharmaceutical Science, Babasaheb Bhimrao Ambedkar University (A Central university), Vidya Vihar, Raebareli Road, Lucknow - 226 025, Uttar Pradesh
|How to cite this article:|
Rehman M, Agarwal V, Sharma K, Mishra V. Epigenetic Regulation in Mesial Temporal Lobe Epilepsy Associated with Hippocampal Sclerosis.Neurol India 2020;68:314-315
|How to cite this URL:|
Rehman M, Agarwal V, Sharma K, Mishra V. Epigenetic Regulation in Mesial Temporal Lobe Epilepsy Associated with Hippocampal Sclerosis. Neurol India [serial online] 2020 [cited 2022 Jul 2 ];68:314-315
Available from: https://www.neurologyindia.com/text.asp?2020/68/2/314/284369
Mesial temporal lobe epilepsy (MTLE) accounts for almost 80% of all temporal lobe epilepsy (TLE) in which seizures originate from the medial or internal structures of the temporal lobe. The most common finding associated with MTLE is hippocampal sclerosis (HS), identified as a shrunken hippocampus on magnetic resonance imaging (MRI). MTLE is also most likely to be pharmacoresistant and anterior temporal lobectomy offers the best possibility of a seizure-free life with reduced reliance on antiepileptic drugs. The etiology of HS is multifactorial and widely considered to be an acquired phenomenon, secondary to postnatal injury resulting from prolonged febrile seizures or head trauma. Experimental studies revealed neuronal damage and gliosis in HS cause alterations in neuronal connectivity and enhanced excitability that contributes to epileptogenesis. The aberrant network restructuring and hyperexcitability have been associated with large scale changes in gene transcription and protein expression. The genome-wide expression profiling studies in experimental and human epilepsy had revealed alteration in genes coding for ion channels, synaptic remodelling, inflammation, gliosis and neuronal death. Moreover, several genome-wide studies also support evidence that epilepsy progression is accompanied by large scale epigenetic modifications such as altered DNA methylation in TLE. The neurobiological aspects of MTLE are still unresolved; nevertheless, DNA methylation can be an important regulator of gene expression changes associated with the development of MTLE with HS.
In this study, Dixitet al. evaluated the methylation regulated gene expression in HS patients sample by correlating the differential methylation pattern to differential gene expression. The Genome-wide DNA methylation analysis was performed by Human DNA Methylation Microarray and compared for samples from 4 HS patients and two autopsy cases to non-epileptic control. Differential gene expression analysis was performed using RNAseq methodology and Cuffdiff software. The integrative analysis of DNA methylation and gene expression was performed using gene spring software GX version 13.0. The Differential gene expression (DGE) analysis revealed the upregulation and downregulation of a number of genes in HS patients and their integration with hypomethylated and hypermethylated genes. Interestingly, authors reported a total of 66 DEGs genes inversely correlating with the promotor methylation patterns of which promotors of 26 down-regulated DEGs were hypermethylated and 40 upregulated DEGs were hypomethylated. The authors also report increased mRNA expression levels of DNA Methyl transferase one which is primarily associated with the maintenance of DNA methylation. However, the mRNA levels for DNA Methyl transferase three that is associated with the addition of new methylation marks remained unaltered. Interestingly Zhu et al., found increased expression of both DNMT1 as well as DNMT3a protein in hippocampal tissues of TLE patients. These studies suggest that DNA methylation mediated epigenetic regulation is involved in the development of MTLE associated with HS.
Dixit et al. also performed functional gene clustering and network analysis of inversely correlated genes that revealed epigenetically regulated canonical pathways associated with HS. The 66 inversely correlated genes were mostly associated with neuronal development (SEMA3B, NRP1), cell-cell interactions (TFAP2A), ion channel dysfunction (CACNG2), protein kinases and cell signaling (ADAM17, MAP3K11, TTBK1). The most important signaling pathways identified were axon guidance mediated by semaphorins, ionotropic glutamate receptor pathway, and notch signaling pathways. Miller-Delaneyet al. had also found altered DNA methylation for 146 genes in the hippocampus of TLE patients with hippocampal sclerosis, and 81.5% of the promoters of those genes displayed hypermethylation. Gene ontology analysis revealed that these genes were involved in neural development, neuron remodeling, neuron maturation, neurotransmitter/synaptic transmission, and cell death functions. However, the association between methylation state and expression of the affected genes was found to be weak. Guelfi et al. had also performed a whole (gene and exon-level) transcriptome analysis on a large cohort of a cortical tissue sample and identified a large number of genes that are differently expressed between MTLE tissue and controls. The downregulated genes in the MTLE with HS were mainly related to neuron development, differentiation and synaptic signaling and the upregulated genes were instead related to immune response and vascular development.
Dixit et al. have for the first time, reported epigenetically deregulated genes, and discussed the pathways with a potential role in the pathophysiology of HS patients. This study along with other studies, suggests abnormal DNA methylation has functional consequences in MTLE with HS.,,, Moreover, identification of the mechanisms that regulate the transcription of genes that mediate epilepsy progression may open new perspectives for the treatment of drug-resistant MTLE and the prevention of epileptogenesis.
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