Polyadenylation of mRNA as a novel regulatory mechanism of gene expression in temporal lobe epilepsy.

Abstract

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 >25% 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.

• Authors: Alberto Parras, Laura de Diego-Garcia, Mariana Alves, Edward Beamer, Giorgia Conte, Eva M Jimenez-Mateos, James Morgan, Ivana Ollà, Yasmina Hernandez-Santana, Norman Delanty, Michael A Farrell, Donncha F O'Brien, Alejandro Ocampo, David C Henshall, Raúl Méndez, José J Lucas, Tobias Engel
• Journal: Brain : a journal of neurology (Brain) Vol. 143 Issue 7 Pg. 2139-2153 (07 01 2020) ISSN: 1460-2156 [Electronic] England
• PMID: 32594159 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: [email protected].

Chemical References

• CPEB4 protein, human
• Cpeb4 protein, mouse
• RNA, Messenger
• RNA-Binding Proteins

Topics

• Animals
• Epilepsy, Temporal Lobe (genetics, metabolism)
• Female
• Gene Expression Regulation (physiology)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Polyadenylation (physiology)
• RNA, Messenger (metabolism)
• RNA-Binding Proteins (metabolism)