Stress-related methylation of the catechol-O-methyltransferase Val 158 allele predicts human prefrontal cognition and activity (original) (raw)
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DNA methylation impacts on learning and memory in aging
Neurobiology of Aging, 2009
Learning and memory are two of the fundamental cognitive functions that confer us the ability to accumulate knowledge from our experiences. Although we use these two mental skills continuously, understanding the molecular basis of learning and memory is very challenging. Methylation modification of DNA is an epigenetic mechanism that plays important roles in regulating gene expression, which is one of the key processes underlying the functions of cells including neurons. Interestingly, a genome-wide decline in DNA methylation occurs in the brain during normal aging, which coincides with a functional decline in learning and memory with age. It has been speculated that DNA methylation in neurons might be involved in memory coding. However, direct evidence supporting the role of DNA methylation in memory formation is still under investigation. This particular function of DNA methylation has not drawn wide attention despite several important studies that have provided supportive evidence for the epigenetic control of memory formation. To facilitate further exploration of the epigenetic basis of memory function, we will review existing studies on DNA methylation that are related to the development and function of the nervous system. We will focus on studies illustrating how DNA methylation regulates neural activities and memory formation via the control of gene expression in neurons, and relate these studies to various age-related neurological disorders that affect cognitive functions.
The Role of DNA Methylation in the Central Nervous System and Neuropsychiatric Disorders
International Review of Neurobiology, 2009
DNA methylation is an epigenetic mechanism in which the methyl group is covalently coupled to the C5 position of the cytosine residue of CpG dinucleotides. DNA methylation generally leads to gene silencing and is catalyzed by a group of enzymes known as DNA methyltransferases (Dnmt). During development, the epigenome undergoes waves of demethylation and methylation changes. As a result, there are cell type/tissue-specific DNA methylation patterns. Since DNA methylation changes only happen during DNA replication to maintain methylation patterns on hemimethylated DNA or establish new methylation, Dnmt expression generally decreases greatly after cell division. However, significant levels of Dnmts were noticed specifically in postmitotic neurons, suggesting a functional importance of Dnmt in the nervous system. Accumulating evidence showed that DNA methylation correlates with certain neuropsychiatric disorders such as schizophrenia, Rett syndrome, and ICF syndrome. Studies of methyl-CpG-binding proteins, Dnmt inhibitors, and Dnmt knockout mice also explored the key role of DNA methylation in neural development, plasticity, learning, and memory. Though an enzyme exhibiting DNA demethylation capability in vertebrates still remains to be identified, DNA methylation status in the CNS appeared to be reversible at certain genomic loci. This supports a maintenance role of Dnmt to prevent active demethylation in postmitotic neurons. Taken together, DNA methylation provides an epigenetic mechanism of gene regulation in neural development, function, and disorders. INTERNATIONAL REVIEW OF 67 NEUROBIOLOGY, VOL. 89
DNA Methylation Signatures in Development and Aging of the Human Prefrontal Cortex
The American Journal of Human Genetics, 2012
The human prefrontal cortex (PFC), a mastermind of the brain, is one of the last brain regions to mature. To investigate the role of epigenetics in the development of PFC, we examined DNA methylation in~14,500 genes at~27,000 CpG loci focused on 5 0 promoter regions in 108 subjects range in age from fetal to elderly. DNA methylation in the PFC shows unique temporal patterns across life. The fastest changes occur during the prenatal period, slow down markedly after birth and continue to slow further with aging. At the genome level, the transition from fetal to postnatal life is typified by a reversal of direction, from demethylation prenatally to increased methylation postnatally. DNA methylation is strongly associated with genotypic variants and correlates with expression of a subset of genes, including genes involved in brain development and in de novo DNA methylation. Our results indicate that promoter DNA methylation in the human PFC is a highly dynamic process modified by genetic variance and regulating gene transcription. Additional discovery is made possible with a stand-alone application, BrainCloudMethyl.
DNA methylation and cognitive functioning in healthy older adults
Knowledge, Technology & Policy, 2012
Long-term supplementation with folic acid may improve cognitive performance in older individuals. The relationship between folate status and cognitive performance might be mediated by changes in methylation capacity, as methylation reactions are important for normal functioning of the brain. Although aberrant DNA methylation has been implicated in neurodevelopmental disorders, the relationship between DNA methylation status and non-pathological cognitive functioning in human subjects has not yet been investigated. The present study investigated the associations between global DNA methylation and key domains of cognitive functioning in healthy older adults. Global DNA methylation, defined as the percentage of methylated cytosine to total cytosine, was measured in leucocytes by liquid chromatography -MS/MS, in 215 men and women, aged 50-70 years, who participated in the Folic Acid and Carotid Intima-Media Thickness (FACIT) study (clinical trial registration number NCT00110604). Cognitive performance was assessed by means of the Visual Verbal Word Learning Task, the Stroop Colour-Word Interference Test, the Concept Shifting Test, the Letter-Digit Substitution Test and the Verbal Fluency Test. Using hierarchical linear regression analyses adjusted for age, sex, level of education, alcohol consumption, smoking status, physical activity, erythrocyte folate concentration and 5,10-methylenetetrahydrofolate reductase 677 C ! T genotype, we found that global DNA methylation was not related to cognitive performance on any of the domains measured. The present study results do not support the hypothesis that global DNA methylation, as measured in leucocytes, might be associated with cognitive functioning in healthy older individuals.
Journal of Neuroscience, 2008
The COMT (catechol-O-methyltransferase) gene has been linked to a spectrum of human phenotypes, including cognition, anxiety, pain sensitivity and psychosis. Doubts about its clinical impact exist, however, because of the complexity of human COMT polymorphism and clinical variability. We generated transgenic mice overexpressing a human COMT-Val polymorphism (Val-tg), and compared them with mice containing a null COMT mutation. Increased COMT enzyme activity in Val-tg mice resulted in disrupted attentional set-shifting abilities, and impaired working and recognition memory, but blunted stress responses and pain sensitivity. Conversely, COMT disruption improved working memory, but increased stress responses and pain sensitivity. Amphetamine ameliorated recognition memory deficits in COMT-Val-tg mice but disrupted it in wild types, illustrating COMT modulation of the inverted-U relationship between cognition and dopamine. COMT-Val-tg mice showed increased prefrontal cortex (PFC) calcium/calmodulin-dependent protein kinase II (CaMKII) levels, whereas COMT deficiency decreased PFC CaMKII but increased PFC CaMKK and CaMKIV levels, suggesting the involvement of PFC CaMK pathways in COMT-regulated cognitive function and adaptive stress responses. Our data indicate a critical role for the COMT gene in an apparent evolutionary trade-off between cognitive and affective functions. neered mice lacking functional COMT and a new transgenic mouse overexpressing the human COMT-Val variant, and compared them to normal wild-type COMT-Leu mice. This approach allowed us to contrast life-long effects of genetic variation resulting in relatively low and relatively high COMT activity, respectively. Furthermore, in an effort to identify molecular mechanisms of cognitive effects, we examined the impact of COMT genetic modifications on the expression of components of the Ca 2ϩ /calmodulin-dependent protein kinase superfamily (CaMK), which have been linked to learning and memory processes .
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2010
Post-traumatic stress disorder (PTSD) is unique among psychiatric disorders since there is an explicit requirement for the presence of a well-defined precipitating environmental event. This suggests the participation of adaptable molecular processes such as epigenetic modifications, including acetylation and methylation of histones and DNA methylation. In the present study we investigated whether changes in DNA methylation are associated with the effects of traumatic stressor, using a validated PTSD rat model. Screening of genomic DNA methylation patterns revealed that maladaptation to traumatic stress is associated with numerous changes in the methylation pattern of rat hippocampus. Of the differentially methylated genes revealed by this global screening, Disks Large-Associated Protein (Dlgap2) was of special interest, demonstrating an increase in a specific methylation site which was associated with a reduction in its gene expression in PTSD-like compared to non-PTSD-like rats. Th...
Environmentally induced epigenetic alterations are related to mental health. We investigated quantitative DNA methylation status before and after an acute psychosocial stressor in two stress-related genes: oxytocin receptor (OXTR) and brain-derived neurotrophic factor (BDNF). The cross sectional study took place at the Division of Theoretical and Clinical Psychobiology, University of Trier, Germany and was conducted from February to August 2009. We included 83 participants aged 61-67 years. Thereof, 76 participants completed the full study procedure consisting of blood sampling before (pre-stress), 10 min after (post-stress) and 90 min after (follow-up) the Trier social stress test. We assessed quantitative DNA methylation of whole-blood cells using Sequenom EpiTYPER. Methylation status differed between sampling times in one target sequence of OXTR (Po0.001): methylation increased from pre-to post-stress (P ¼ 0.009) and decreased from post-stress to follow-up (Po0.001). This decrease was also found in a second target sequence of OXTR (P ¼ 0.034), where it lost statistical significance when blood cell count was statistically controlled. We did not detect any time-associated differences in methylation status of the examined BDNF region. The results suggest a dynamic regulation of DNA methylation in OXTR-which may in part reflect changes in blood cell composition-but not BDNF after acute psychosocial stress. This may enhance the understanding of how psychosocial events alter DNA methylation and could provide new insights into the etiology of mental disorders.
Cortical DNA methylation maintains remote memory
A behavioral memory's lifetime represents multiple molecular lifetimes, suggesting the necessity for a self-perpetuating signal. One candidate is DNA methylation, a transcriptional repression mechanism that maintains cellular memory throughout development. We found that persistent, gene-specific cortical hypermethylation was induced in rats by a single, hippocampus-dependent associative learning experience and pharmacologic inhibition of methylation 1 month after learning disrupted remote memory. We propose that the adult brain utilizes DNA methylation to preserve long-lasting memories.
PLoS ONE, 2007
The role of DNA cytosine methylation, an epigenetic regulator of chromatin structure and function, during normal and pathological brain development and aging remains unclear. Here, we examined by MethyLight PCR the DNA methylation status at 50 loci, encompassing primarily 59 CpG islands of genes related to CNS growth and development, in temporal neocortex of 125 subjects ranging in age from 17 weeks of gestation to 104 years old. Two psychiatric disease cohortsdefined by chronic neurodegeneration (Alzheimer's) or lack thereof (schizophrenia)-were included. A robust and progressive rise in DNA methylation levels across the lifespan was observed for 8/50 loci (GABRA2, GAD1, HOXA1, NEUROD1, NEUROD2, PGR, STK11, SYK) typically in conjunction with declining levels of the corresponding mRNAs. Another 16 loci were defined by a sharp rise in DNA methylation levels within the first few months or years after birth. Disease-associated changes were limited to 2/50 loci in the Alzheimer's cohort, which appeared to reflect an acceleration of the age-related change in normal brain. Additionally, methylation studies on sorted nuclei provided evidence for bidirectional methylation events in cortical neurons during the transition from childhood to advanced age, as reflected by significant increases at 3, and a decrease at 1 of 10 loci. Furthermore, the DNMT3a de novo DNA methyl-transferase was expressed across all ages, including a subset of neurons residing in layers III and V of the mature cortex. Therefore, DNA methylation is dynamically regulated in the human cerebral cortex throughout the lifespan, involves differentiated neurons, and affects a substantial portion of genes predominantly by an age-related increase.