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.