Large-scale changes to mRNA polyadenylation in temporal lobe epilepsy

Temporal lobe epilepsy is the most common and refractory form of epilepsy in adults. Gene expression within affected structures\nsuch as the hippocampus displays extensive dysregulation and is implicated as a central pathomechanism. Post-transcriptional\nmechanisms are increasingly recognized as determinants of the gene expression landscape, but key mechanisms remain unexplored.\nHere we show, for first time, that cytoplasmic mRNA polyadenylation, one of the post-transcriptional mechanisms regulating\ngene expression, undergoes widespread reorganization in temporal lobe epilepsy. In the hippocampus of mice subjected to status\nepilepticus and epilepsy, we report 425% of the transcriptome displays changes in their poly(A) tail length, with deadenylation\ndisproportionately affecting genes previously associated with epilepsy. Suggesting cytoplasmic polyadenylation element binding\nproteins (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\nover-represented among transcripts with poly(A) tail alterations and epilepsy-related genes and CPEB4 expression was found to be\nincreased in mouse models of seizures and resected hippocampi from patients with drug-refractory temporal lobe epilepsy. Finally,\nsupporting an adaptive function for CPEB4, deletion of Cpeb4 exacerbated seizure severity and neurodegeneration during status\nepilepticus 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.