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Large-scale changes to mRNA polyadenylation in temporal lobe epilepsy

journal contribution
posted on 10.07.2020 by Alberto Parras Rodriguez, Laura De Diego Garcia, Mariana Alves, Edward Beamer, Giorgia Conte, Eva M Jimenez-Mateos, James Morgan, ivana olla, Yasmina Hernandez-Santana, Norman Delanty, Michael A Farrell, Donncha F. O'Brien, Alejandro Ocampo, David Henshall, Raul Mendez de la Iglesia, jose J Lucas, Tobias Engel
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.

Funding

This work was supported by funding from the Health Research Board HRA-POR-2015-1243 to T.E.; Science Foundation Ireland (13/SIRG/2098 and 17/CDA/4708 to T.E and co-funded under the European Regional Development Fund and by FutureNeuro industry partners 16/RC/3948 to D.C.H); from the H2020 Marie Skłodowska-Curie Actions Individual Fellowship (796600 to L.D-G and 753527 to E.B), from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement (No. 766124 to T.E.), from ISCIII-CiberNed collaborative grants PI2015-2/06-3 and PI2018/06-1 to J.J.L. and by MINECO/MCIU grants SAF2015-65371-R and RTI2018-096322-B-I00 to J.J.L. from the MINECO/MCIU (BFU2017-83561-P), the Fundación BBVA, the Fundación Bancaria “la Caixa”, the Fundación La marato TV3 and the Scientific Foundation of the Spanish Association Against Cancer (AECC) to R.M. CBMSO is also funded by an institutional grant from Fundación Ramón Areces. A.P. was recipient of a CIBERNED-Ayuda a la movilidad and Spark grant (SNSF) CRSK-3_190764/1. IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain) and is supported by the CERCA Programme (Catalan Government).

History

Published Citation

Parras A, Diego-Garcia L, Alves M, Beamer E, Conte G, Jimenez-Mateos EM, Morgan J, Ollà I, Hernandez-Santana Y, Delanty N, Farrell MA, O’Brien DF, Ocampo A, Henshall DC, Méndez R, Lucas JJ, Engel T. Polyadenylation of mRNA as a novel regulatory mechanism of gene expression in temporal lobe epilepsy. Brain. 2020: 28 June [epub before print]

Publication Date

28/06/2020

Department/Unit

  • Physiology and Medical Physics

Research Area

  • Neurological and Psychiatric Disorders

Publisher

Oxford University Press

Version

  • Submitted Version (Preprint)

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