Epigenetic silencing of OR and TAS2R genes expression in human orbitofrontal cortex at early stages of sporadic Alzheimer’s disease

Modulation of brain olfactory (OR) and taste receptor (TASR) expression was recently reported in neurological diseases. However, there is still limited evidence of these genes' expression in the human brain and the transcriptional regulation mechanisms involved remain elusive. We explored the p...

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Autores: Alves, Victoria da Cunha, Figueiró Silva, Joana, Ferrer, Isidro (Ferrer Abizanda), Carro, Eva
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/201421
Acceso en línea:https://hdl.handle.net/2445/201421
Access Level:acceso abierto
Palabra clave:Malaltia d'Alzheimer
Epigenètica
Alzheimer's disease
Epigenetics
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spelling Epigenetic silencing of OR and TAS2R genes expression in human orbitofrontal cortex at early stages of sporadic Alzheimer’s diseaseAlves, Victoria da CunhaFigueiró Silva, JoanaFerrer, Isidro (Ferrer Abizanda)Carro, EvaMalaltia d'AlzheimerEpigenèticaAlzheimer's diseaseEpigeneticsModulation of brain olfactory (OR) and taste receptor (TASR) expression was recently reported in neurological diseases. However, there is still limited evidence of these genes' expression in the human brain and the transcriptional regulation mechanisms involved remain elusive. We explored the possible expression and regulation of selected OR and TASR in the human orbitofrontal cortex (OFC) of sporadic Alzheimer's disease (AD) and non-demented control specimens using quantitative real-time RT-PCR and ELISA. Global H3K9me3 amounts were measured on OFC total histone extracts, and H3K9me3 binding at each chemoreceptor locus was examined through native chromatin immunoprecipitation. To investigate the potential interactome of the repressive histone mark H3K9me3 in OFC specimens, native nuclear complex co-immunoprecipitation (Co-IP) was combined with reverse phase-liquid chromatography coupled to mass spectrometry analysis. Interaction between H3K9me3 and MeCP2 was validated by reciprocal Co-IP, and global MeCP2 levels were quantitated. We found that OR and TAS2R genes are expressed and markedly downregulated in OFC at early stages of sporadic AD, preceding the progressive reduction in their protein levels and the appearance of AD-associated neuropathology. The expression pattern did not follow disease progression suggesting transcriptional regulation through epigenetic mechanisms. We discovered an increase of OFC global H3K9me3 levels and a substantial enrichment of this repressive signature at ORs and TAS2Rs proximal promoter at early stages of AD, ultimately lost at advanced stages. We revealed the interaction between H3K9me3 and MeCP2 at early stages and found that MeCP2 protein is increased in sporadic AD. Findings suggest MeCP2 might be implicated in OR and TAS2R transcriptional regulation through interaction with H3K9me3, and as an early event, it may uncover a novel etiopathogenetic mechanism of sporadic AD.Springer Science and Business Media LLC2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/201421Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1007/s00018-023-04845-1Cellular and Molecular Life Sciences, 2023, vol. 80, num. 8https://doi.org/10.1007/s00018-023-04845-1cc by (c) Alves, Victoria da Cunha et al, 2023http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2014212026-05-27T06:46:51Z
dc.title.none.fl_str_mv Epigenetic silencing of OR and TAS2R genes expression in human orbitofrontal cortex at early stages of sporadic Alzheimer’s disease
title Epigenetic silencing of OR and TAS2R genes expression in human orbitofrontal cortex at early stages of sporadic Alzheimer’s disease
spellingShingle Epigenetic silencing of OR and TAS2R genes expression in human orbitofrontal cortex at early stages of sporadic Alzheimer’s disease
Alves, Victoria da Cunha
Malaltia d'Alzheimer
Epigenètica
Alzheimer's disease
Epigenetics
title_short Epigenetic silencing of OR and TAS2R genes expression in human orbitofrontal cortex at early stages of sporadic Alzheimer’s disease
title_full Epigenetic silencing of OR and TAS2R genes expression in human orbitofrontal cortex at early stages of sporadic Alzheimer’s disease
title_fullStr Epigenetic silencing of OR and TAS2R genes expression in human orbitofrontal cortex at early stages of sporadic Alzheimer’s disease
title_full_unstemmed Epigenetic silencing of OR and TAS2R genes expression in human orbitofrontal cortex at early stages of sporadic Alzheimer’s disease
title_sort Epigenetic silencing of OR and TAS2R genes expression in human orbitofrontal cortex at early stages of sporadic Alzheimer’s disease
dc.creator.none.fl_str_mv Alves, Victoria da Cunha
Figueiró Silva, Joana
Ferrer, Isidro (Ferrer Abizanda)
Carro, Eva
author Alves, Victoria da Cunha
author_facet Alves, Victoria da Cunha
Figueiró Silva, Joana
Ferrer, Isidro (Ferrer Abizanda)
Carro, Eva
author_role author
author2 Figueiró Silva, Joana
Ferrer, Isidro (Ferrer Abizanda)
Carro, Eva
author2_role author
author
author
dc.subject.none.fl_str_mv Malaltia d'Alzheimer
Epigenètica
Alzheimer's disease
Epigenetics
topic Malaltia d'Alzheimer
Epigenètica
Alzheimer's disease
Epigenetics
description Modulation of brain olfactory (OR) and taste receptor (TASR) expression was recently reported in neurological diseases. However, there is still limited evidence of these genes' expression in the human brain and the transcriptional regulation mechanisms involved remain elusive. We explored the possible expression and regulation of selected OR and TASR in the human orbitofrontal cortex (OFC) of sporadic Alzheimer's disease (AD) and non-demented control specimens using quantitative real-time RT-PCR and ELISA. Global H3K9me3 amounts were measured on OFC total histone extracts, and H3K9me3 binding at each chemoreceptor locus was examined through native chromatin immunoprecipitation. To investigate the potential interactome of the repressive histone mark H3K9me3 in OFC specimens, native nuclear complex co-immunoprecipitation (Co-IP) was combined with reverse phase-liquid chromatography coupled to mass spectrometry analysis. Interaction between H3K9me3 and MeCP2 was validated by reciprocal Co-IP, and global MeCP2 levels were quantitated. We found that OR and TAS2R genes are expressed and markedly downregulated in OFC at early stages of sporadic AD, preceding the progressive reduction in their protein levels and the appearance of AD-associated neuropathology. The expression pattern did not follow disease progression suggesting transcriptional regulation through epigenetic mechanisms. We discovered an increase of OFC global H3K9me3 levels and a substantial enrichment of this repressive signature at ORs and TAS2Rs proximal promoter at early stages of AD, ultimately lost at advanced stages. We revealed the interaction between H3K9me3 and MeCP2 at early stages and found that MeCP2 protein is increased in sporadic AD. Findings suggest MeCP2 might be implicated in OR and TAS2R transcriptional regulation through interaction with H3K9me3, and as an early event, it may uncover a novel etiopathogenetic mechanism of sporadic AD.
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/201421
url https://hdl.handle.net/2445/201421
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1007/s00018-023-04845-1
Cellular and Molecular Life Sciences, 2023, vol. 80, num. 8
https://doi.org/10.1007/s00018-023-04845-1
dc.rights.none.fl_str_mv cc by (c) Alves, Victoria da Cunha et al, 2023
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Alves, Victoria da Cunha et al, 2023
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Science and Business Media LLC
publisher.none.fl_str_mv Springer Science and Business Media LLC
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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