Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder

Bipolar disorder (BD) is a severe mental disorder characterized by repeated mood swings. Although genetic factors are collectively associated with the etiology of BD, the underlying molecular mechanisms, particularly how environmental factors affect the brain, remain largely unknown. We performed pr...

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Autores principales: Bundo, Miki, Ueda, Junko, Nakachi, Yutaka, Kasai, Kiyoto, Kato, Tadafumi, Iwamoto, Kazuya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505249/
https://www.ncbi.nlm.nih.gov/pubmed/33875800
http://dx.doi.org/10.1038/s41380-021-01079-0
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author Bundo, Miki
Ueda, Junko
Nakachi, Yutaka
Kasai, Kiyoto
Kato, Tadafumi
Iwamoto, Kazuya
author_facet Bundo, Miki
Ueda, Junko
Nakachi, Yutaka
Kasai, Kiyoto
Kato, Tadafumi
Iwamoto, Kazuya
author_sort Bundo, Miki
collection PubMed
description Bipolar disorder (BD) is a severe mental disorder characterized by repeated mood swings. Although genetic factors are collectively associated with the etiology of BD, the underlying molecular mechanisms, particularly how environmental factors affect the brain, remain largely unknown. We performed promoter-wide DNA methylation analysis of neuronal and nonneuronal nuclei in the prefrontal cortex of patients with BD (N = 34) and controls (N = 35). We found decreased DNA methylation at promoters in both cell types in the BD patients. Gene Ontology (GO) analysis of differentially methylated region (DMR)-associated genes revealed enrichment of molecular motor-related genes in neurons, chemokines in both cell types, and ion channel- and transporter-related genes in nonneurons. Detailed GO analysis further revealed that growth cone- and dendrite-related genes, including NTRK2 and GRIN1, were hypermethylated in neurons of BD patients. To assess the effect of medication, neuroblastoma cells were cultured under therapeutic concentrations of three mood stabilizers. We observed that up to 37.9% of DMRs detected in BD overlapped with mood stabilizer-induced DMRs. Interestingly, mood stabilizer-induced DMRs showed the opposite direction of changes in DMRs, suggesting the therapeutic effects of mood stabilizers. Among the DMRs, 12 overlapped with loci identified in a genome-wide association study (GWAS) of BD. We also found significant enrichment of neuronal DMRs in the loci reported in another GWAS of BD. Finally, we performed qPCR of DNA methylation-related genes and found that DNMT3B was overexpressed in BD. The cell-type-specific DMRs identified in this study will be useful for understanding the pathophysiology of BD.
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spelling pubmed-85052492021-10-22 Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder Bundo, Miki Ueda, Junko Nakachi, Yutaka Kasai, Kiyoto Kato, Tadafumi Iwamoto, Kazuya Mol Psychiatry Article Bipolar disorder (BD) is a severe mental disorder characterized by repeated mood swings. Although genetic factors are collectively associated with the etiology of BD, the underlying molecular mechanisms, particularly how environmental factors affect the brain, remain largely unknown. We performed promoter-wide DNA methylation analysis of neuronal and nonneuronal nuclei in the prefrontal cortex of patients with BD (N = 34) and controls (N = 35). We found decreased DNA methylation at promoters in both cell types in the BD patients. Gene Ontology (GO) analysis of differentially methylated region (DMR)-associated genes revealed enrichment of molecular motor-related genes in neurons, chemokines in both cell types, and ion channel- and transporter-related genes in nonneurons. Detailed GO analysis further revealed that growth cone- and dendrite-related genes, including NTRK2 and GRIN1, were hypermethylated in neurons of BD patients. To assess the effect of medication, neuroblastoma cells were cultured under therapeutic concentrations of three mood stabilizers. We observed that up to 37.9% of DMRs detected in BD overlapped with mood stabilizer-induced DMRs. Interestingly, mood stabilizer-induced DMRs showed the opposite direction of changes in DMRs, suggesting the therapeutic effects of mood stabilizers. Among the DMRs, 12 overlapped with loci identified in a genome-wide association study (GWAS) of BD. We also found significant enrichment of neuronal DMRs in the loci reported in another GWAS of BD. Finally, we performed qPCR of DNA methylation-related genes and found that DNMT3B was overexpressed in BD. The cell-type-specific DMRs identified in this study will be useful for understanding the pathophysiology of BD. Nature Publishing Group UK 2021-04-20 2021 /pmc/articles/PMC8505249/ /pubmed/33875800 http://dx.doi.org/10.1038/s41380-021-01079-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Bundo, Miki
Ueda, Junko
Nakachi, Yutaka
Kasai, Kiyoto
Kato, Tadafumi
Iwamoto, Kazuya
Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder
title Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder
title_full Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder
title_fullStr Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder
title_full_unstemmed Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder
title_short Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder
title_sort decreased dna methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505249/
https://www.ncbi.nlm.nih.gov/pubmed/33875800
http://dx.doi.org/10.1038/s41380-021-01079-0
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