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Stress-Related Methylation of the Catechol- O -Methyltransferase Val 158 Allele Predicts Human Prefrontal Cognition and Activity
Open accessAbstract
DNA methylation at CpG dinucleotides is associated with gene silencing, stress, and memory. The catechol-O-methyltransferase (COMT) Val(158) allele in rs4680 is associated with differential enzyme activity, stress responsivity, and prefrontal activity during working memory (WM), and it creates a CpG dinucleotide. We report that methylation of the Val(158) allele measured from peripheral blood mononuclear cells (PBMCs) of Val/Val humans is associated negatively with lifetime stress and positively with WM performance; it interacts with stress to modulate prefrontal activity during WM, such that greater stress and lower methylation are related to reduced cortical efficiency; and it is inversely related to mRNA expression and protein levels, potentially explaining the in vivo effects. Finally, methylation of COMT in prefrontal cortex and that in PBMCs of rats are correlated. The relationship of methylation of the COMT Val(158) allele with stress, gene expression, WM performance, and related brain activity suggests that stress-related methylation is associated with silencing of the gene, which partially compensates the physiological role of the high-activity Val allele in prefrontal cognition and activity. Moreover, these results demonstrate how stress-related DNA methylation of specific functional alleles impacts directly on human brain physiology beyond sequence variation.
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“In rats, a direct correlation between catechol-O-methyltransferase (COMT) methylation in peripheral mononuclear blood cells and the prefrontal cortex was observed (Ursini et al., 2011).”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Ursini et al., 2011
In the citing paper
“as several studies indicate its role in stress reactivity on a genetic [46,47] and epigenetic level [48].”
From Dynamic DNA methylation changes in the COMT gene promoter region in response to mental stress and its modulation by transcranial direct current stimulation (2021) · cites this paper as [48]
In the citing paper
“Indeed, for COMT DNAm several studies show that methylation status in peripheral tissue can serve as surrogate for brain DNAm [48,50].”
From Dynamic DNA methylation changes in the COMT gene promoter region in response to mental stress and its modulation by transcranial direct current stimulation (2021) · cites this paper as [48]
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“In Val homozygotes increased lifetime stress was found to correlate with reduced methylation that in turn correlated with poorer working memory performance (94).”
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“…EpiTYPER DNA methylation of one target sequence of OXTR was increased from pre- to poststress (10min) and decreased from post-stress to follow-up (90min) Ursini et al. 2011 n ¼ 84 84 healthy 84 Caucasian 32 male 52 female Peripheral blood COMT Pyrosequencing Methylation of the COMT Val158…”
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Metadata
- Authors
- Ursini, G., Bollati, V., Fazio, L., Porcelli, A., Iacovelli, L., Catalani, A., Sinibaldi, L., Gelao, B., Romano, R., Rampino, A., Taurisano, P., Mancini, M., Di Giorgio, A., Popolizio, T., Baccarelli, A., De Blasi, A., Blasi, G., & Bertolino, A.
- Affiliations
- University of Bari Aldo Moro (IT)
- University of Milan (IT)
- Sapienza University of Rome (IT)
- Casa Sollievo della Sofferenza (IT)
- Harvard University (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-05-04
- Volume
- 31
- Issue
- 18
- Pages
- 6692-6698
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6632869
- OpenAlex
- W2008679805
- Cited by
- 188
- References
- 61
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 7 · 2022: 4 · 2021: 12 · 2020: 14 · 2019: 10 · 2018: 9 · 2017: 17 · 2016: 25 · 2015: 13 · 2014: 20 · 2013: 16 · 2012: 22
- FWCI
- 8.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- catechol-O-methyltransferase, DNA methylation, CpG, working memory, prefrontal cortex, gene silencing, epigenetics, peripheral blood mononuclear cells, gene expression, enzyme activity, rats
- MeSH terms
- Adult, Alleles, Animals, Catechol O-Methyltransferase, Cognition, Female, Genotype, Humans, Magnetic Resonance Imaging, Male, Memory, Short-Term, Neuropsychological Tests, Polymorphism, Genetic, Surveys and Questionnaires, Stress, Psychological, Blotting, Western, Rats, Wistar, Prefrontal Cortex, DNA Methylation, Reverse Transcriptase Polymerase Chain Reaction, Rats
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