Multiomics analysis of the regulome and transcriptome at the single-cell resolution in mesial temporal lobe epilepsy with hippocampal sclerosis

Abstract

Patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE+HS) are frequently resistant to treatment with antiseizure drugs (ASD). Epilepsy surgery may be an efficient treatment for these patients. However, not all patients respond well to surgery. Currently, there are no biomarkers to predict response to ASD or prognosis after epilepsy surgery. We hypothesize that gene expression's epigenomic regulation may play a role in response to ASD and surgical outcome in patients with MTLE+HS. Therefore, we propose investigating the genomic regulatory elements and the gene expression patterns using multi-omic single-nucleus ATAC-seq + RNA-seq in brain tissue resected by epilepsy surgery. For this, we will evaluate the open chromatin regions and transcriptome of hippocampal tissue from patients with ASD refractory epilepsy and correlate this with clinical and imaging findings in the pre- and postoperative period. We will divide patients into two groups of up to 8 patients: group 1, patients without seizures for at least e2 years after surgery, and group 2 patients with seizures in the same period. We expect our results to identify genomic regulatory factors at the single-cell level, which, combined with clinical information, will identify cell-specific signatures and epigenetic elements associated with surgical prognosis and the biology of ASD resistant MTLE+HS. In addition, these findings will be combined with those obtained in previous studies by our research group on the tissue methylome profiling and circulating biomarkers in MTLE+HS. To our knowledge, this will be the first study using single-nucleus ATAC-seq and RNA-seq in MTLE+HS, and we expect that our results may contribute significantly to a better understanding of cell heterogeneity and epigenomic regulation in MTLE+HS as it relates to different treatment modalities. Furthermore, we will contribute to the ongoing international efforts to map cell heterogeneity in normal and disease statues, such as the Human Cell Atlas (https://www.humancellatlas.org/). (AU)