The Site Specific Demethylation in the 5′-Regulatory Area of NMDA Receptor 2B Subunit Gene Associated with CIE-Induced Up-Regulation of Transcription

Mei, Qiang; Denny, Ashley D.; Chen, Jiguo; Ticku, Maharaj K.; Yan, Bo; Henderson, George I.

doi:10.1371/journal.pone.0008798

Cited by 54 publications

(59 citation statements)

References 75 publications

(117 reference statements)

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“…We examined two genes that have been associated with neuronal plasticity and psychopathology and are known to be epigenetically regulated in response to environmental exposures: brain-derived neurotrophic factor (Bdnf) (21)(22)(23)(24) and NMDA receptor 2b subunit (Grin2b) (25,26). In addition, we also examined expression of the epigenetic regulators implicated in DNA (de) methylation in the brain: growth arrest and DNA damage-inducible beta (Gadd45b) (27) at P28 and P60, and DNA methyltransferases 1 (Dnmt1) and -3a (Dnmt3a) (28) at P60.…”

Section: Resultsmentioning

confidence: 99%

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DNA methylation of BDNF as a biomarker of early-life adversity

Kundaković

Gudsnuk

Herbstman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

349

238

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Early-life adversity increases the risk for psychopathology in later life. The underlying mechanism(s) is unknown, but epigenetic variation represents a plausible candidate. Early-life exposures can disrupt epigenetic programming in the brain, with lasting consequences for gene expression and behavior. This evidence is primarily derived from animal studies, with limited study in humans due to inaccessibility of the target brain tissue. In humans, although there is evidence for DNA methylation changes in the peripheral blood of psychiatric patients, a fundamental question remains as to whether epigenetic markers in the blood can predict epigenetic changes occurring in the brain. We used in utero bisphenol A (BPA) exposure as a model environmental exposure shown to disrupt neurodevelopment and exert long-term effects on behavior in animals and humans. We show that prenatal BPA induces lasting DNA methylation changes in the transcriptionally relevant region of the Bdnf gene in the hippocampus and blood of BALB/c mice and that these changes are consistent with BDNF changes in the cord blood of humans exposed to high maternal BPA levels in utero. Our data suggest that BDNF DNA methylation in the blood may be used as a predictor of brain BDNF DNA methylation and gene expression as well as behavioral vulnerability induced by early-life environmental exposure. Because BDNF expression and DNA methylation are altered in several psychiatric disorders that are associated with early-life adversity, including depression, schizophrenia, bipolar disorder, and autism, BDNF DNA methylation in the blood may represent a novel biomarker for the early detection of psychopathology.epigenetics | biomarker | BDNF | bisphenol A | early life

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Section: Resultsmentioning

confidence: 99%

“…The examined region of Grin2b also contains a CREB-binding site ( Fig. 2E) and is sensitive to DNA methylation (25). Therefore, Fig.…”

Section: P28 (mentioning

confidence: 95%

DNA methylation of BDNF as a biomarker of early-life adversity

Kundaković

Gudsnuk

Herbstman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

349

238

View full text Add to dashboard Cite

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“…Therefore, this enhanced GluN2B subunit expression translates to greater functional GluN2B-containing receptors. This enhanced expression is likely related to the persistent up-regulation of GluN2B gene expression via DNA demethylation (Sheela Rani and Ticku 2006;Qiang et al 2010). In conjunction with these changes in the GluN2B subunit, chronic ethanol also increases expression of the GluN1 subunit (Follesa and Ticku 1996; Kalluri et al 1998;Floyd et al 2003;Hendricson et al 2007;Qiang et al 2007) and in a few cases GluN2A (Follesa and Ticku 1996; Kalluri et al 1998).…”

Section: Chronic Ethanol Effects On Nmdarsmentioning

confidence: 99%

Ethanol Effects on N-Methyl-D-Aspartate Receptors in the Bed Nucleus of the Stria Terminalis

Wills

Winder

2013

Cold Spring Harbor Perspectives in Medicine

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The extended amygdala is a series of interconnected, embryologically similar series of nuclei in the brain that are thought to play key roles in aspects of alcohol dependence, specifically in stress-induced increases in alcohol-seeking behaviors. Plasticity of excitatory transmission in these and other brain regions is currently an intense area of scrutiny as a mechanism underlying aspects of addiction. N-methyl-D-aspartate (NMDA) receptors (NMDARs) play a critical role in plasticity at excitatory synapses and have been identified as major molecular targets of ethanol. Thus, this article will explore alcohol and NMDAR interactions first at a general level and then focusing within the extended amygdala, in particular on the bed nucleus of the stria terminalis (BNST).

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“…It is now known that AID is also necessary for dynamic reprogramming of pluripotent stem cells (Bhutani et al, 2010) and, based on its ability to promote Tet1-mediated hydroxylation of methylated cytosine , this enzyme has been implicated in active DNA demethylation (Morgan, Dean, Coker, Reik, & Petersen-Mahrt, 2004;Rai et al, 2008;Fig. 1b).…”

Section: Activation-induced Cytidine Deaminase (Aid)mentioning

confidence: 99%

“…The T-G mismatch is recognized by the DNA glycosylases TDG or MBD4, together with their binding partner Gadd45a. Studies in zebrafish have suggested that AID, MBD4 and GADD45a can cooperate in demethylating a methylated DNA duplex (Rai et al, 2008). A tertiary complex between TDG, AID, and GADD45a has also been identified, which is thought to coordinate BER-mediated DNA demethylation (Cortellino et al, 2011).…”

Section: Methyl-cpg-binding Domain Protein 4 (Mbd4)mentioning

confidence: 99%

Tet-mediated DNA hydroxymethylation within the prefrontal cortex as a mechanism for the formation and maintenance of fear-related memory

Li¹

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Anxiety disorders are characterized by a significant impairment in one's ability to inhibit or control their fear in response to cues that remind them of the initiating traumatic event. On the other hand, fear extinction is the gradual reduction in fear response, which occurs through repeated presentation of non-reinforced fear-related cues. Fear extinction is therefore an important evolutionarily conserved behavioural adaptation that is essential for survival. The evidence indicates that the infralimbic region of the medial prefrontal cortex (ILPFC) plays a critical role in the acquisition and maintenance of fear extinction memory; however, the cellular and molecular mechanisms involved in the formation and maintenance of fear extinction memory have not been fully elucidated.Epigenetic mechanisms are critically involved in the regulation of gene expression underlying learning and memory. Dynamic variation in cytosine methylation has emerged as a primary mechanism underlying experience-dependent plasticity in the nervous system and in the formation of fear-related memory. However, cytosine methylation is not the only DNA modification in eukaryotic genome. Recent studies have shown that 5-methylcytosine (5mC) can be oxidized and converted to 5-hydroxymethylaton (5hmC) by the ten-eleven translocation (Tet) family proteins. Moreover, 5hmC has been found to be highly enriched in the adult brain, can be dynamically regulated by neural activity, and accumulates across the lifespan. In this thesis, I build upon the hypothesis that Tet-mediated accumulation of 5hmC may underpin the novel cellular and molecular processes that contribute to fear extinction memory. In support of this hypothesis, I first demonstrate that Tet3 gene expression is associated with neuronal activation in vitro. We next found that the expression of Tet3 mRNA, not Tet1 mRNA, is specifically induced after fear extinction training, in vivo. Interestingly, by blocking fear extinction with the NMDA antagonist, MK-801, we found that learning-induced Tet3 mRNA expression is inhibited. Furthermore, lentiviral-mediated knockdown of Tet3 inhibits the consolidation of fear extinction memory.These data strongly suggest that Tet3 is critical for fear extinction memory.To expand on these findings, we performed high-throughput genome-wide sequencing for 5hmC. This was enabled by sequencing samples derived from the infralimibic prefrontal cortex (ILPFC) of mice. We developed a novel protocol that allows one to profile the genome-wide landscape of 5hmC within the ILPFC of individual mice using low input DNA.By adopting this protocol, we mapped out the accumulation of 5hmC across the genome in the ILPFC following fear acquisition and fear extinction. We have found that, upon 2 behavioural training, there is a dramatic redistribution of 5hmC in response to learning.Moreover, by comparing the genome-wide data between fear conditioned and fear extinction-trained mice, we identified 233 unique genomic loci that exhibit accumulation of 5hmC after extinction tra...

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The Site Specific Demethylation in the 5′-Regulatory Area of NMDA Receptor 2B Subunit Gene Associated with CIE-Induced Up-Regulation of Transcription

Cited by 54 publications

References 75 publications

DNA methylation of BDNF as a biomarker of early-life adversity

DNA methylation of BDNF as a biomarker of early-life adversity

Ethanol Effects on N-Methyl-D-Aspartate Receptors in the Bed Nucleus of the Stria Terminalis

Tet-mediated DNA hydroxymethylation within the prefrontal cortex as a mechanism for the formation and maintenance of fear-related memory

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