Dados do Trabalho

Título

Genome-wide methylation profile of brain tissue from patients with mesial temporal lobe epilepsy with hippocampal sclerosis

Introdução

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE+HS) is adults' most frequent and severe epilepsy. When patients with MTLE+HS do not respond to treatment with anti-seizure medication, one may consider epilepsy surgery. The tissue resected by surgery has been extensively studied, and we and others have demonstrated abnormal gene expression in MTLE+HS. Gene expression is complex and regulated by many molecular mechanisms, including DNA methylation.

Objetivo

Therefore, we aim to investigate whether changes determined by DNA methylation are present in brain tissue resected from patients with MTLE+HS and how they could impact gene expression dynamics.

Método

We performed whole-genome bisulfite sequencing to analyze DNA from 11 brain samples obtained by epilepsy surgery from patients with medically refractory MTLE+HS. We compared these to data obtained from samples of four autopsy controls (hippocampus and dentate gyrus). Samples from patients were divided into two groups: i) patients with less than 20 years of disease duration (G1 - n = 5); and ii) patients with more than 20 years of disease duration (G2 - n = 6). Methylome was assessed using whole-genome sequencing in an Illumina® platform, and differentially methylated regions (DMRs) were identified. We conducted two by two comparisons between data from patients and controls and between the two groups of patients. Furthermore, we catalog the putative genes located in the DMRs.

Resultados

Overall hypermethylation was observed in tissue from patients. Also, DMRs had a heterogeneous distribution, usually affecting more than one genomic region. Still, introns and promoters had increased DMRs compared to other regions. Furthermore, we identified many genes in the DMRs for the comparisons performed (6,371 in G1 x Controls; 5,548 in G2 x Control; and 4,088 for G1 x G2).

Conclusão

Currently, DNA methylation can be analyzed using high throughput methods to determine its distribution in the entire human genome, the so-called methylome. This analysis gives an overview of gene regulation mediated by methylation. We found significant changes in the methylome of the brain tissue in patients with MTLE+HS, with thousands of DMRs in patients. These were related to many candidate genes potentially involved in the molecular mechanisms underlying MTLE+HS. Furthermore, our results indicate that the molecular abnormalities present in HS change over time.

Palavras-chave

Methylome; Epilepsy; WGBS; Brain Tissue; MTLE