Exposure to extrinsic stressors, social defeat or bisphenol A, eliminates sex differences in DNA methyltransferase expression in the amygdala

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Abstract

Chemical and psychological stressors can exert long lasting changes in brain function and behavior. Changes in DNA methylation have been shown to be an important mechanism mediating long lasting changes in neural function and behavior, especially for anxiety-like or stress responses. Here we examined the effects of either a social or chemical stressor on DNA methyltransferase (DNMT) gene expression in the amygdala, an important brain region modulating stress responses and anxiety. In adult California mice ( Peromyscus californicus) that were naïve to social defeat, females had higher levels of Dnmt1 expression in punch samples of the central amygdala (CeA) than males. In addition, social defeat stress reduced Dnmt1 and Dnmt3a expression in the CeA of females but not males. A second study using more anatomically specific punch samples replicated these effects for Dnmt1. Perinatal exposure, spanning from periconception through lactation, to bisphenol A or ethinyl estradiol (estrogens in birth control pills) also abolished sex differences in Dnmt1 expression in the CeA but not basolateral amygdala. These findings identify a robust sex difference in Dnmt1 expression in the CeA that is sensitive to both psychological and chemical stressors. Our results suggest that future studies should examine the impact of psychological and chemical stressors on DNA methylation in the CeA and that Dnmt1 may have an underappreciated role in plasticity in behavior.

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Lasting epigenetic influence of early-life adversity on the BDNF gene.

Tania L. Roth, Farah D. Lubin, Adam J Funk … (2009)

Childhood maltreatment and early trauma leave lasting imprints on neural mechanisms of cognition and emotion. With a rat model of infant maltreatment by a caregiver, we investigated whether early-life adversity leaves lasting epigenetic marks at the brain-derived neurotrophic factor (BDNF) gene in the central nervous system. During the first postnatal week, we exposed infant rats to stressed caretakers that predominately displayed abusive behaviors. We then assessed DNA methylation patterns and gene expression throughout the life span as well as DNA methylation patterns in the next generation of infants. Early maltreatment produced persisting changes in methylation of BDNF DNA that caused altered BDNF gene expression in the adult prefrontal cortex. Furthermore, we observed altered BDNF DNA methylation in offspring of females that had previously experienced the maltreatment regimen. These results highlight an epigenetic molecular mechanism potentially underlying lifelong and transgenerational perpetuation of changes in gene expression and behavior incited by early abuse and neglect.

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DNA methylation, methyltransferases, and cancer.

K D Robertson (2001)

The field of epigenetics has recently moved to the forefront of studies relating to diverse processes such as transcriptional regulation, chromatin structure, genome integrity, and tumorigenesis. Recent work has revealed how DNA methylation and chromatin structure are linked at the molecular level and how methylation anomalies play a direct causal role in tumorigenesis and genetic disease. Much new information has also come to light regarding the cellular methylation machinery, known as the DNA methyltransferases, in terms of their roles in mammalian development and the types of proteins they are known to interact with. This information has forced a new view for the role of DNA methyltransferases. Rather than enzymes that act in isolation to copy methylation patterns after replication, the types of interactions discovered thus far indicate that DNA methyltransferases may be components of larger complexes actively involved in transcriptional control and chromatin structure modulation. These new findings will likely enhance our understanding of the myriad roles of DNA methylation in disease as well as point the way to novel therapies to prevent or repair these defects.

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Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens

Quincey LaPlant, Vincent Vialou, Herbert Covington … (2010)

Despite abundant expression of DNA methyltransferases (Dnmt’s) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We find that Dnmt3a expression is regulated in mouse nucleus accumbens (NAc) by chronic cocaine and chronic social defeat stress. Moreover, NAc specific manipulations that block DNA methylation potentiate cocaine reward and exert antidepressant-like effects, whereas NAc specific Dnmt3a overexpression attenuates cocaine reward and is pro-depressant. On a cellular level, we show that chronic cocaine selectively increases thin dendritic spines on NAc neurons and that DNA methylation is both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli.