Identification of EP300 as a Key Gene Involved in Antipsychotic-Induced Metabolic Dysregulation Based on Integrative Bioinformatics Analysis of Multi-Tissue Gene Expression Data

Antipsychotics (APs) are associated with weight gain and other metabolic abnormalities such as hyperglycemia, dyslipidemia and metabolic syndrome. This translational study aimed to uncover the underlying molecular mechanisms and identify the key genes involved in AP-induced metabolic effects. An int...

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Autores: Martínez Pinteño, Albert, Gassó Astorga, Patricia, Prohens Coll, Llucia, Gonzàlez Segura, Àlex, Parellada, Mara, Saiz Ruiz, Jerónimo, Cuesta, Manuel J., Bernardo Arroyo, Miquel, Lafuente, Amàlia, 1952-2022, Mas Herrero, Sergi, Rodríguez Ferret, Natalia
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/185011
Acceso en línea:https://hdl.handle.net/2445/185011
Access Level:acceso abierto
Palabra clave:Farmacogenètica
Teràpia genètica
Antipsicòtics
Pharmacogenetics
Gene therapy
Antipsychotic drugs
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spelling Identification of EP300 as a Key Gene Involved in Antipsychotic-Induced Metabolic Dysregulation Based on Integrative Bioinformatics Analysis of Multi-Tissue Gene Expression DataMartínez Pinteño, AlbertGassó Astorga, PatriciaProhens Coll, LluciaGonzàlez Segura, ÀlexParellada, MaraSaiz Ruiz, JerónimoCuesta, Manuel J.Bernardo Arroyo, MiquelLafuente, Amàlia, 1952-2022Mas Herrero, SergiRodríguez Ferret, NataliaFarmacogenèticaTeràpia genèticaAntipsicòticsPharmacogeneticsGene therapyAntipsychotic drugsAntipsychotics (APs) are associated with weight gain and other metabolic abnormalities such as hyperglycemia, dyslipidemia and metabolic syndrome. This translational study aimed to uncover the underlying molecular mechanisms and identify the key genes involved in AP-induced metabolic effects. An integrative gene expression analysis was performed in four different mouse tissues (striatum, liver, pancreas and adipose) after risperidone or olanzapine treatment. The analytical approach combined the identification of the gene co-expression modules related to AP treatment, gene set enrichment analysis and protein-protein interaction network construction. We found several co-expression modules of genes involved in glucose and lipid homeostasis, hormone regulation and other processes related to metabolic impairment. Among these genes, EP300, which encodes an acetyltransferase involved in transcriptional regulation, was identified as the most important hub gene overlapping the networks of both APs. Then, we explored the genetically predicted EP300 expression levels in a cohort of 226 patients with first-episode psychosis who were being treated with APs to further assess the association of this gene with metabolic alterations. The EP300 expression levels were significantly associated with increases in body weight, body mass index, total cholesterol levels, low-density lipoprotein cholesterol levels and triglyceride concentrations after 6 months of AP treatment. Taken together, our analysis identified EP300 as a key gene in AP-induced metabolic abnormalities, indicating that the dysregulation of EP300 function could be important in the development of these side effects. However, more studies are needed to disentangle the role of this gene in the mechanism of action of APs. Keywords: EP300; antipsychotics; gene; gene expression; metabolic syndrome; microarray; pharmacogenetics; weight gain.Frontiers Media2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/185011Articles publicats en revistes (Fonaments Clínics)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.3389/fphar.2021.729474Frontiers in Pharmacology, 2021, vol. 12, p. 729474https://doi.org/10.3389/fphar.2021.729474cc-by (c) Martinez Pinteño, Albert et al., 2021https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1850112026-05-27T06:46:51Z
dc.title.none.fl_str_mv Identification of EP300 as a Key Gene Involved in Antipsychotic-Induced Metabolic Dysregulation Based on Integrative Bioinformatics Analysis of Multi-Tissue Gene Expression Data
title Identification of EP300 as a Key Gene Involved in Antipsychotic-Induced Metabolic Dysregulation Based on Integrative Bioinformatics Analysis of Multi-Tissue Gene Expression Data
spellingShingle Identification of EP300 as a Key Gene Involved in Antipsychotic-Induced Metabolic Dysregulation Based on Integrative Bioinformatics Analysis of Multi-Tissue Gene Expression Data
Martínez Pinteño, Albert
Farmacogenètica
Teràpia genètica
Antipsicòtics
Pharmacogenetics
Gene therapy
Antipsychotic drugs
title_short Identification of EP300 as a Key Gene Involved in Antipsychotic-Induced Metabolic Dysregulation Based on Integrative Bioinformatics Analysis of Multi-Tissue Gene Expression Data
title_full Identification of EP300 as a Key Gene Involved in Antipsychotic-Induced Metabolic Dysregulation Based on Integrative Bioinformatics Analysis of Multi-Tissue Gene Expression Data
title_fullStr Identification of EP300 as a Key Gene Involved in Antipsychotic-Induced Metabolic Dysregulation Based on Integrative Bioinformatics Analysis of Multi-Tissue Gene Expression Data
title_full_unstemmed Identification of EP300 as a Key Gene Involved in Antipsychotic-Induced Metabolic Dysregulation Based on Integrative Bioinformatics Analysis of Multi-Tissue Gene Expression Data
title_sort Identification of EP300 as a Key Gene Involved in Antipsychotic-Induced Metabolic Dysregulation Based on Integrative Bioinformatics Analysis of Multi-Tissue Gene Expression Data
dc.creator.none.fl_str_mv Martínez Pinteño, Albert
Gassó Astorga, Patricia
Prohens Coll, Llucia
Gonzàlez Segura, Àlex
Parellada, Mara
Saiz Ruiz, Jerónimo
Cuesta, Manuel J.
Bernardo Arroyo, Miquel
Lafuente, Amàlia, 1952-2022
Mas Herrero, Sergi
Rodríguez Ferret, Natalia
author Martínez Pinteño, Albert
author_facet Martínez Pinteño, Albert
Gassó Astorga, Patricia
Prohens Coll, Llucia
Gonzàlez Segura, Àlex
Parellada, Mara
Saiz Ruiz, Jerónimo
Cuesta, Manuel J.
Bernardo Arroyo, Miquel
Lafuente, Amàlia, 1952-2022
Mas Herrero, Sergi
Rodríguez Ferret, Natalia
author_role author
author2 Gassó Astorga, Patricia
Prohens Coll, Llucia
Gonzàlez Segura, Àlex
Parellada, Mara
Saiz Ruiz, Jerónimo
Cuesta, Manuel J.
Bernardo Arroyo, Miquel
Lafuente, Amàlia, 1952-2022
Mas Herrero, Sergi
Rodríguez Ferret, Natalia
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Farmacogenètica
Teràpia genètica
Antipsicòtics
Pharmacogenetics
Gene therapy
Antipsychotic drugs
topic Farmacogenètica
Teràpia genètica
Antipsicòtics
Pharmacogenetics
Gene therapy
Antipsychotic drugs
description Antipsychotics (APs) are associated with weight gain and other metabolic abnormalities such as hyperglycemia, dyslipidemia and metabolic syndrome. This translational study aimed to uncover the underlying molecular mechanisms and identify the key genes involved in AP-induced metabolic effects. An integrative gene expression analysis was performed in four different mouse tissues (striatum, liver, pancreas and adipose) after risperidone or olanzapine treatment. The analytical approach combined the identification of the gene co-expression modules related to AP treatment, gene set enrichment analysis and protein-protein interaction network construction. We found several co-expression modules of genes involved in glucose and lipid homeostasis, hormone regulation and other processes related to metabolic impairment. Among these genes, EP300, which encodes an acetyltransferase involved in transcriptional regulation, was identified as the most important hub gene overlapping the networks of both APs. Then, we explored the genetically predicted EP300 expression levels in a cohort of 226 patients with first-episode psychosis who were being treated with APs to further assess the association of this gene with metabolic alterations. The EP300 expression levels were significantly associated with increases in body weight, body mass index, total cholesterol levels, low-density lipoprotein cholesterol levels and triglyceride concentrations after 6 months of AP treatment. Taken together, our analysis identified EP300 as a key gene in AP-induced metabolic abnormalities, indicating that the dysregulation of EP300 function could be important in the development of these side effects. However, more studies are needed to disentangle the role of this gene in the mechanism of action of APs. Keywords: EP300; antipsychotics; gene; gene expression; metabolic syndrome; microarray; pharmacogenetics; weight gain.
publishDate 2021
dc.date.none.fl_str_mv 2021
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/2445/185011
url https://hdl.handle.net/2445/185011
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/10.3389/fphar.2021.729474
Frontiers in Pharmacology, 2021, vol. 12, p. 729474
https://doi.org/10.3389/fphar.2021.729474
dc.rights.none.fl_str_mv cc-by (c) Martinez Pinteño, Albert et al., 2021
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Martinez Pinteño, Albert et al., 2021
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv Articles publicats en revistes (Fonaments Clínics)
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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