CPEB4–CLOCK crosstalk during temporal lobe epilepsy
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. Previo...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/346753 |
| Acceso en línea: | http://hdl.handle.net/10261/346753 |
| Access Level: | acceso abierto |
| Palabra clave: | Circadian rhythm CLOCK CPEB4 Cytoplasmic polyadenylation Epilepsy Status epilepticus |
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España |
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| dc.title.none.fl_str_mv |
CPEB4–CLOCK crosstalk during temporal lobe epilepsy |
| title |
CPEB4–CLOCK crosstalk during temporal lobe epilepsy |
| spellingShingle |
CPEB4–CLOCK crosstalk during temporal lobe epilepsy de Diego-Garcia, Laura Circadian rhythm CLOCK CPEB4 Cytoplasmic polyadenylation Epilepsy Status epilepticus |
| title_short |
CPEB4–CLOCK crosstalk during temporal lobe epilepsy |
| title_full |
CPEB4–CLOCK crosstalk during temporal lobe epilepsy |
| title_fullStr |
CPEB4–CLOCK crosstalk during temporal lobe epilepsy |
| title_full_unstemmed |
CPEB4–CLOCK crosstalk during temporal lobe epilepsy |
| title_sort |
CPEB4–CLOCK crosstalk during temporal lobe epilepsy |
| dc.creator.none.fl_str_mv |
de Diego-Garcia, Laura Brennan, Gary P Auer, Theresa Menendez-Mendez, Aida Parras, Alberto Martin-Gil, Alba Mitra, Meghma Ollà, Ivana Villalba-Benito, Leticia Gil, Beatriz Alves, Mariana Lau, Kelvin Delanty, Norman Beausang, Alan Cryan, Jane Brett, Francesca M. Farrell, Michael A. O'Brien, Donncha F. Mendez, Raúl Carracedo-Rodríguez, Gonzalo Henshall, David C Lucas, José J Engel, Tobias |
| author |
de Diego-Garcia, Laura |
| author_facet |
de Diego-Garcia, Laura Brennan, Gary P Auer, Theresa Menendez-Mendez, Aida Parras, Alberto Martin-Gil, Alba Mitra, Meghma Ollà, Ivana Villalba-Benito, Leticia Gil, Beatriz Alves, Mariana Lau, Kelvin Delanty, Norman Beausang, Alan Cryan, Jane Brett, Francesca M. Farrell, Michael A. O'Brien, Donncha F. Mendez, Raúl Carracedo-Rodríguez, Gonzalo Henshall, David C Lucas, José J Engel, Tobias |
| author_role |
author |
| author2 |
Brennan, Gary P Auer, Theresa Menendez-Mendez, Aida Parras, Alberto Martin-Gil, Alba Mitra, Meghma Ollà, Ivana Villalba-Benito, Leticia Gil, Beatriz Alves, Mariana Lau, Kelvin Delanty, Norman Beausang, Alan Cryan, Jane Brett, Francesca M. Farrell, Michael A. O'Brien, Donncha F. Mendez, Raúl Carracedo-Rodríguez, Gonzalo Henshall, David C Lucas, José J Engel, Tobias |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
European Commission Irish Research Council Comunidad de Madrid Science Foundation Ireland Ministerio de Economía y Competitividad (España) Ministerio de Ciencia, Innovación y Universidades (España) Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
Circadian rhythm CLOCK CPEB4 Cytoplasmic polyadenylation Epilepsy Status epilepticus |
| topic |
Circadian rhythm CLOCK CPEB4 Cytoplasmic polyadenylation Epilepsy Status epilepticus |
| description |
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. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 2024 2024 2024 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/346753 |
| url |
http://hdl.handle.net/10261/346753 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
#PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/EC/H2020/766124 info:eu-repo/grantAgreement/EC/H2020/796600 info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-123141OB-I00 2020-T2/BMD-20180/ProgramadeAtraccióndeTalento-CM http://dx.doi.org/10.1111/epi.17736 Sí |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.publisher.none.fl_str_mv |
John Wiley & Sons |
| publisher.none.fl_str_mv |
John Wiley & Sons |
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reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC) |
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Consejo Superior de Investigaciones Científicas (CSIC) |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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1869405971905773568 |
| spelling |
CPEB4–CLOCK crosstalk during temporal lobe epilepsyde Diego-Garcia, LauraBrennan, Gary PAuer, TheresaMenendez-Mendez, AidaParras, AlbertoMartin-Gil, AlbaMitra, MeghmaOllà, IvanaVillalba-Benito, LeticiaGil, BeatrizAlves, MarianaLau, KelvinDelanty, NormanBeausang, AlanCryan, JaneBrett, Francesca M.Farrell, Michael A.O'Brien, Donncha F.Mendez, RaúlCarracedo-Rodríguez, GonzaloHenshall, David CLucas, José JEngel, TobiasCircadian rhythmCLOCKCPEB4Cytoplasmic polyadenylationEpilepsyStatus epilepticusObjective: 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.H2020 Marie Skłodowska-Curie Actions, Grant/Award Number:766124 and 796600; Irish Research Council, Grant/Award Number:GOIPD/2020/806; Programa de Atracción de Talento de la Comunidad de Madrid, Grant/Award Number: 2020-T2/BMD- 20180; Science Foundation Ireland, Grant/Award Number:16/RC/3948 and 17/CDA/4708;Spanish Ministry of Economy and Competitiveness/Ministry of Science, Innovation and Universities, Grant/Award Number: PID2021- 123141OB- I00Peer reviewedJohn Wiley & SonsEuropean CommissionIrish Research CouncilComunidad de MadridScience Foundation IrelandMinisterio de Economía y Competitividad (España)Ministerio de Ciencia, Innovación y Universidades (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2024202420232024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/346753reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/EC/H2020/766124info:eu-repo/grantAgreement/EC/H2020/796600info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-123141OB-I002020-T2/BMD-20180/ProgramadeAtraccióndeTalento-CMhttp://dx.doi.org/10.1111/epi.17736Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3467532026-05-22T06:33:51Z |
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15,812455 |