Dados do Trabalho

Título

Robust changes in genomic methylation found in mesial temporal lobe epilepsy

Resumo

Introduction: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE+HS) is the most frequent and severe epilepsy in adults. When patients with MTLE+HS do not respond to clinical treatment, 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 epigenetic changes. Therefore, we aim to investigate whether epigenetic changes determined by DNA methylation are present in brain tissue resected from patients with MTLE+HS.
Materials and Methods: 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 performed 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.
Results: Overall hypermethylation was observed in tissue from patients. Also, DMRs had a heterogeneous distribution throughout the genome, and these were usually observed in more than one region, depending on their length, but introns and promoters had increased DMRs compared to other genomic regions. 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).
Discussion/Conclusion: 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 a complete overview of gene regulation mediated by methylation. We found remarkable 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