10779/rcsi.12630608.v1 Alberto Parras Rodriguez Alberto Parras Rodriguez Laura De Diego Garcia Laura De Diego Garcia Mariana Alves Mariana Alves Edward Beamer Edward Beamer Giorgia Conte Giorgia Conte Eva M Jimenez-Mateos Eva M Jimenez-Mateos James Morgan James Morgan ivana olla ivana olla Yasmina Hernandez-Santana Yasmina Hernandez-Santana Norman Delanty Norman Delanty Michael A Farrell Michael A Farrell Donncha F. O'Brien Donncha F. O'Brien Alejandro Ocampo Alejandro Ocampo David Henshall David Henshall Raul Mendez de la Iglesia Raul Mendez de la Iglesia jose J Lucas jose J Lucas Tobias Engel Tobias Engel Large-scale changes to mRNA polyadenylation in temporal lobe epilepsy Royal College of Surgeons in Ireland 2020 Temporal lobe epilepsy (TLE) mRNA polyadenylation neurological disease Seizures CPEB family members Neuroscience 2020-07-10 14:16:29 Preprint https://repository.rcsi.com/articles/preprint/Large-scale_changes_to_mRNA_polyadenylation_in_temporal_lobe_epilepsy/12630608 Temporal lobe epilepsy is the most common and refractory form of epilepsy in adults. Gene expression within affected structures such as the hippocampus displays extensive dysregulation and is implicated as a central pathomechanism. Post-transcriptional mechanisms are increasingly recognized as determinants of the gene expression landscape, but key mechanisms remain unexplored. Here we show, for first time, that cytoplasmic mRNA polyadenylation, one of the post-transcriptional mechanisms regulating gene expression, undergoes widespread reorganization in temporal lobe epilepsy. In the hippocampus of mice subjected to status epilepticus and epilepsy, we report 425% of the transcriptome displays changes in their poly(A) tail length, with deadenylation disproportionately affecting genes previously associated with epilepsy. Suggesting cytoplasmic polyadenylation element binding proteins (CPEBs) being one of the main contributors to mRNA polyadenylation changes, transcripts targeted by CPEBs were particularly enriched among the gene pool undergoing poly(A) tail alterations during epilepsy. Transcripts bound by CPEB4 were over-represented among transcripts with poly(A) tail alterations and epilepsy-related genes and CPEB4 expression was found to be increased in mouse models of seizures and resected hippocampi from patients with drug-refractory temporal lobe epilepsy. Finally, supporting an adaptive function for CPEB4, deletion of Cpeb4 exacerbated seizure severity and neurodegeneration during status epilepticus and the development of epilepsy in mice. Together, these findings reveal an additional layer of gene expression regulation during epilepsy and point to novel targets for seizure control and disease-modification in epilepsy.