Role of CBP and p300 in the establishment and maintenance of transcriptional programs in adult excitatory neurons

The paralog lysine acetyltransferases (KAT) CREB binding protein (CBP) and E1A binding protein (p300) are both essential for the normal development of the nervous system, but their specific function in post-mitotic neurons remain unclear. To investigate these functions, we produced inducible forebra...

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Detalles Bibliográficos
Autor: Lipinski, Michal
Tipo de recurso: tesis doctoral
Fecha de publicación:2019
País:España
Institución:Universidad Miguel Hernández de Elche
Repositorio:REDIUMH. Depósito Digital de la UMH
OAI Identifier:oai:dspace.umh.es:11000/30259
Acceso en línea:https://hdl.handle.net/11000/30259
Access Level:acceso abierto
Palabra clave:Neurociencias
CDU::6 - Ciencias aplicadas::61 - Medicina::616 - Patología. Medicina clínica. Oncología::616.8 - Neurología. Neuropatología. Sistema nervioso
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spelling Role of CBP and p300 in the establishment and maintenance of transcriptional programs in adult excitatory neuronsLipinski, MichalNeurocienciasCDU::6 - Ciencias aplicadas::61 - Medicina::616 - Patología. Medicina clínica. Oncología::616.8 - Neurología. Neuropatología. Sistema nerviosoThe paralog lysine acetyltransferases (KAT) CREB binding protein (CBP) and E1A binding protein (p300) are both essential for the normal development of the nervous system, but their specific function in post-mitotic neurons remain unclear. To investigate these functions, we produced inducible forebrain-specific knockout mice for either one or both proteins. When both KATs were knocked out simultaneously in the adult brain, but not after individual ablation, mice showed a rapid deterioration, severe neurological phenotypes and premature death. These phenotypes were associated with the reduction of once-acquired dendritic complexity and electrical activity in excitatory neurons, which correlates with the transcriptional shutdown of neuronal genes and a dramatic loss of H3K27 acetylation and occupancy by pro-neural transcription factors at neuronal enhancers. Targeted lysine acetylation using the CRISPR/dCas9 system restituted neuronal-specific gene expression. These experiments demonstrate that KAT3 proteins are necessary for maintaining neuronal identity and function in the adult brain by preserving correct chromatin acetylation levels. Further insight into the phenotype of a single-KAT3 induced forebrain knockouts showed that a homozygous loss of a CBP caused a highly specific phenotype in cognition, transcription and histone acetylation. Meanwhile, the modest changes in histone acetylation caused homozygous loss of p300 did not correlate with any changes in behavior or gene expression. Interestingly, the difference between CBP and p300 was highlighted when mice were exposed to a neuroadaptive paradigm like environmental enrichment or pro-epileptic drug sensitization. Whereas the p300 knockouts again did not show any difference from the control littermates, the CBP knockout mice were unable to adapt to the environmental change. This effect was paralleled by a failure in induction a specific gene expression programs induced in control mice as a result of the challenge. Therefore, CBP and p300 jointly maintain neuro-specific transcriptional programs in adult excitatory neurons, and CBP seems to be vital for shifting these programs in response to experiences or environmental changes.Universidad Miguel HernándezBarco Guerrero, ÁngelLópez-Atalaya, José PascualInstituto de Neurociencias202320232019info:eu-repo/semantics/doctoralThesisapplication/pdf279application/pdfhttps://hdl.handle.net/11000/30259reponame:REDIUMH. Depósito Digital de la UMHinstname:Universidad Miguel Hernández de ElcheInglésinfo:eu-repo/semantics/openAccessAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/oai:dspace.umh.es:11000/302592026-05-27T13:36:21Z
dc.title.none.fl_str_mv Role of CBP and p300 in the establishment and maintenance of transcriptional programs in adult excitatory neurons
title Role of CBP and p300 in the establishment and maintenance of transcriptional programs in adult excitatory neurons
spellingShingle Role of CBP and p300 in the establishment and maintenance of transcriptional programs in adult excitatory neurons
Lipinski, Michal
Neurociencias
CDU::6 - Ciencias aplicadas::61 - Medicina::616 - Patología. Medicina clínica. Oncología::616.8 - Neurología. Neuropatología. Sistema nervioso
title_short Role of CBP and p300 in the establishment and maintenance of transcriptional programs in adult excitatory neurons
title_full Role of CBP and p300 in the establishment and maintenance of transcriptional programs in adult excitatory neurons
title_fullStr Role of CBP and p300 in the establishment and maintenance of transcriptional programs in adult excitatory neurons
title_full_unstemmed Role of CBP and p300 in the establishment and maintenance of transcriptional programs in adult excitatory neurons
title_sort Role of CBP and p300 in the establishment and maintenance of transcriptional programs in adult excitatory neurons
dc.creator.none.fl_str_mv Lipinski, Michal
author Lipinski, Michal
author_facet Lipinski, Michal
author_role author
dc.contributor.none.fl_str_mv Barco Guerrero, Ángel
López-Atalaya, José Pascual
Instituto de Neurociencias
dc.subject.none.fl_str_mv Neurociencias
CDU::6 - Ciencias aplicadas::61 - Medicina::616 - Patología. Medicina clínica. Oncología::616.8 - Neurología. Neuropatología. Sistema nervioso
topic Neurociencias
CDU::6 - Ciencias aplicadas::61 - Medicina::616 - Patología. Medicina clínica. Oncología::616.8 - Neurología. Neuropatología. Sistema nervioso
description The paralog lysine acetyltransferases (KAT) CREB binding protein (CBP) and E1A binding protein (p300) are both essential for the normal development of the nervous system, but their specific function in post-mitotic neurons remain unclear. To investigate these functions, we produced inducible forebrain-specific knockout mice for either one or both proteins. When both KATs were knocked out simultaneously in the adult brain, but not after individual ablation, mice showed a rapid deterioration, severe neurological phenotypes and premature death. These phenotypes were associated with the reduction of once-acquired dendritic complexity and electrical activity in excitatory neurons, which correlates with the transcriptional shutdown of neuronal genes and a dramatic loss of H3K27 acetylation and occupancy by pro-neural transcription factors at neuronal enhancers. Targeted lysine acetylation using the CRISPR/dCas9 system restituted neuronal-specific gene expression. These experiments demonstrate that KAT3 proteins are necessary for maintaining neuronal identity and function in the adult brain by preserving correct chromatin acetylation levels. Further insight into the phenotype of a single-KAT3 induced forebrain knockouts showed that a homozygous loss of a CBP caused a highly specific phenotype in cognition, transcription and histone acetylation. Meanwhile, the modest changes in histone acetylation caused homozygous loss of p300 did not correlate with any changes in behavior or gene expression. Interestingly, the difference between CBP and p300 was highlighted when mice were exposed to a neuroadaptive paradigm like environmental enrichment or pro-epileptic drug sensitization. Whereas the p300 knockouts again did not show any difference from the control littermates, the CBP knockout mice were unable to adapt to the environmental change. This effect was paralleled by a failure in induction a specific gene expression programs induced in control mice as a result of the challenge. Therefore, CBP and p300 jointly maintain neuro-specific transcriptional programs in adult excitatory neurons, and CBP seems to be vital for shifting these programs in response to experiences or environmental changes.
publishDate 2019
dc.date.none.fl_str_mv 2019
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
dc.identifier.none.fl_str_mv https://hdl.handle.net/11000/30259
url https://hdl.handle.net/11000/30259
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
rights_invalid_str_mv Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.format.none.fl_str_mv application/pdf
279
application/pdf
dc.publisher.none.fl_str_mv Universidad Miguel Hernández
publisher.none.fl_str_mv Universidad Miguel Hernández
dc.source.none.fl_str_mv reponame:REDIUMH. Depósito Digital de la UMH
instname:Universidad Miguel Hernández de Elche
instname_str Universidad Miguel Hernández de Elche
reponame_str REDIUMH. Depósito Digital de la UMH
collection REDIUMH. Depósito Digital de la UMH
repository.name.fl_str_mv
repository.mail.fl_str_mv
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