RT Journal Article
T1 CPEB4–CLOCK crosstalk during temporal lobe epilepsy
A1 De Diego García, Laura
A1 Brennan, Gary P.
A1 Auer, Theresa
A1 Menendez-Mendez, Aida
A1 Parras, Alberto
A1 Martín Gil, Alba
A1 Mitra, Meghma
A1 Ollà, Ivana
A1 Villalba-Benito, Leticia
A1 Gil, Beatriz
A1 Alves, Mariana
A1 Lau, Kelvin
AB Objective: Posttranscriptional mechanisms are increasingly recognized as important contributors to the formation of hyperexcitable networks in epilepsy. Messenger RNA (mRNA) polyadenylation is a key regulatory mechanism governing protein expression by enhancing mRNA stability and translation. Previous studies have shown large-scale changes in mRNA polyadenylation in the hippocampus of mice during epilepsy development. The cytoplasmic polyadenylation element-binding protein CPEB4 was found to drive epilepsy-induced poly(A) tail changes, and mice lacking CPEB4 develop a more severe seizure and epilepsy phenotype. The mechanisms controlling CPEB4 function and the downstream pathways that influence the recurrence of spontaneous seizures in epilepsy remain poorly understood. Methods: Status epilepticus was induced in wild-type and CPEB4-deficient male mice via an intra-amygdala microinjection of kainic acid. CLOCK binding to the CPEB4 promoter was analyzed via chromatin immunoprecipitation assay and melatonin levels via high-performance liquid chromatography in plasma. Results: Here, we show increased binding of CLOCK to recognition sites in the CPEB4 promoter region during status epilepticus in mice and increased Cpeb4 mRNA levels in N2A cells overexpressing CLOCK. Bioinformatic analysis of CPEB4-dependent genes undergoing changes in their poly(A) tail during epilepsy found that genes involved in the regulation of circadian rhythms are particularly enriched. Clock transcripts displayed a longer poly(A) tail length in the hippocampus of mice post-status epilepticus and during epilepsy. Moreover, CLOCK expression was increased in the hippocampus in mice post-status epilepticus and during epilepsy, and in resected hippocampus and cortex of patients with drug-resistant temporal lobe epilepsy. Furthermore, CPEB4 is required for CLOCK expression after status epilepticus, with lower levels in CPEB4-deficient compared to wild-type mice. Last, CPEB4-deficient mice showed altered circadian function, including altered melatonin blood levels and altered clustering of spontaneous seizures during the day. Significance: Our results reveal a new positive transcriptional–translational feedback loop involving CPEB4 and CLOCK, which may contribute to the regulation of the sleep–wake cycle during epilepsy.
PB John Wiley & Sons, Inc
SN 0013-9580
YR 2023
FD 2023
LK https://hdl.handle.net/20.500.14352/92454
UL https://hdl.handle.net/20.500.14352/92454
LA eng
NO de Diego-Garcia L, Brennan GP, Auer T, Menendez-Mendez A, Parras A, Martin-Gil A, et al. CPEB4–CLOCK crosstalk during temporal lobe epilepsy. Epilepsia. 2023;00:1–14.
NO Science Foundation Ireland
NO European Commission
NO FutureNeuro industry
NO Irish Research Council
NO Comunidad de Madrid
NO Ministerio de Economía y Competitividad (España)
DS Docta Complutense
RD 6 abr 2025