TY - JOUR
T1 - Stress-related methylation of the catechol-O-methyltransferase val158 allele predicts human prefrontal cognition and activity
AU - Ursini, Gianluca
AU - Bollati, Valentina
AU - Fazio, Leonardo
AU - Porcelli, Annamaria
AU - Iacovelli, Luisa
AU - Catalani, Assia
AU - Sinibaldi, Lorenzo
AU - Gelao, Barbara
AU - Romano, Raffaella
AU - Rampino, Antonio
AU - Taurisano, Paolo
AU - Mancini, Marina
AU - di Giorgio, Annabella
AU - Popolizio, Teresa
AU - Baccarelli, Andrea
AU - de Blasi, Antonio
AU - Blasi, Giuseppe
AU - Bertolino, Alessandro
PY - 2011/5/4
Y1 - 2011/5/4
N2 - DNA methylationatCpG dinucleotides isassociated with gene silencing, stress, and memory. The catechol-O-methyltransferase (COMT) Val158 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 Val158 allele measured from peripheral blood mononuclear cells (PBMCs)ofVal/Valhumans is associated negatively with life time 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 Val158 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.
AB - DNA methylationatCpG dinucleotides isassociated with gene silencing, stress, and memory. The catechol-O-methyltransferase (COMT) Val158 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 Val158 allele measured from peripheral blood mononuclear cells (PBMCs)ofVal/Valhumans is associated negatively with life time 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 Val158 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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U2 - 10.1523/JNEUROSCI.6631-10.2011
DO - 10.1523/JNEUROSCI.6631-10.2011
M3 - Article
C2 - 21543598
AN - SCOPUS:79955782889
SN - 0270-6474
VL - 31
SP - 6692
EP - 6698
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 18
ER -