Increase In Dnmt3a Expression Research Articles

Transgenerational transmission of neurodevelopmental disorders induced by maternal exposure to PM2.5

The pathological traits or diseases susceptibility caused by maternal exposure to environmental adverse insults (infection, malnutrition, environmental toxicants) could be transmitted across generations. It remains uncertain, however, whether the neurodevelopmental disturbances of offspring induced by maternal exposure to PM2.5 during early life can be inherited by subsequent generations without further exposure. In the current study, using transgenerational animal models, we found that F1 female showed poorer performance in Morris Water Maze (MWM), and the deficits in spatial learning and memory similarly presented in F2-F3 female. The transgenerationally-transmitted neurobehavioral disorders were mediated both via maternal and paternal lineage. Since the epigenetic modifications have been reported to be involved in the disturbed neurodevelopment induced by maternal exposure to detrimental environmental factors during early life, we further explored the possible epigenetic mechanism of the transgenerational effects. Intriguingly, the results displayed the significant increase in expression of Dnmt3a in F1 female offspring. And the hypermethylation of Bdnf promoter Ⅳ and downregulated expression of Bdnf in hippocampus were stably transmitted across the generations until the third generation. There was another interesting finding that the transgenerational effects were sex-specific and only emerged in female offspring. Together, our study indicated for the first time that maternal exposure to PM2.5 during early life could detrimentally affect neurobehaviors in multiple generations, and the declined expression of Bdnf induced by hypermethylation of Bdnf promoter Ⅳ mediated by Dnmts might be the potential molecular mechanism.

Effects of chronic restraint stress on the global DNA methylation profile of rat lung cells: Modulation by physical exercise

The potential of behavioral stress to affect epigenetic mechanisms of non-encephalic tissues is still underestimated. In the present study we evaluated the effects of chronic behavioral stress on the DNA methylation profile of rat lung cells. Furthermore, we evaluated the potential of physical exercise to modulate the changes evoked by behavioral stress in lung cells. Male Wistar rats were divided into four experimental groups: (1) animals submitted to chronic restraint stress (CRS) (ST group) during the period of the 67th-80th postnatal day (PND); (2) animals submitted to physical exercise (EX group) during the 53rd-79th PND; (3) animals submitted to swimming during the 53rd-79th PND and to CRS during the 67th-80th PND (EX-ST group); and (4) animals not submitted to stress or swimming protocols (CTL). Global DNA methylation was quantified using an ELISA-based approach and gene expression was evaluated by real time PCR. A decreased global DNA methylation profile was observed in the ST group, however physical exercise demonstrated protection of lung cells from this stress-related hypomethylation. Increased expression of the Dnmt1 gene was evidenced in the ST group, whereas physical exercise was shown to protect lung cells from this stress-related effect in the EX-ST group. Comparative analysis of the ST and EX groups revealed opposite effects on the expression of Dnmt3a and Dnmt3b; however, a stress-related increase in expression of Dnmt3a and Dnmt3b was not seen in the EX-ST group. Our data showed that behavioral stress induced significant changes in the DNA methylation profile of rat lung cells and that this could be modulated by physical exercise.

Epigenetic regulation of Dnmt3a and Arc gene expression after electroconvulsive stimulation in the rat

Electroconvulsive therapy (ECT) remains one of the most effective treatments of major depression. Unfortunately, some patients report side effects, of which the most prominent are memory deficits. The immediate early gene Arc plays a critical role in the maintenance phase of long-term potentiation and consolidation of memory in the rat brain. We recently observed increased methylation of the Arc promoter 24h after acute electroconvulsive stimulation (ECS) in rats, which could cause decreased Arc expression and provide an explanation for the observed memory deficits. In the present study we investigated the methylation and expression changes of Arc at 48h post-ECS and determined the role of de-novo methylation in that process. We initially measured expression of DNA methyltransferases (Dnmt1 and Dnmt3a) and Arc 1, 4, 8, 16, 24, and 48h after a single ECS. Arc expression increased approximately 10-fold at 1 and 4h after ECS, and subsequently decreased below sham levels. Four hours after ECS we also observed a significant increase in Dnmt3a expression, which was attenuated in a second experiment by the use of DNMT inhibitor decitabine (5-aza-2-deoxycytidine). We then investigated Arc gene expression and methylation changes at 48h post-ECS and we found a slightly reduced Arc expression in ECS-treated rats as compared to sham. In animals that received decitabine we observed a significant decrease in Dnmt3a expression and an increase of Arc expression in both ECS and sham groups. The same tendency for reduced Arc expression after ECS, as compared to sham was observed despite the blocking of DNA methylation with decitabine. The DNA methylation as measured by pyrosequencing is decreased 48h post-ECS both in the promoter and intragenic regions as a response to ECS regardless of the treatment with decitabine. Overall the results suggest that DNA methylation is involved in regulating Arc expression but is not the causal mechanism responsible for reducing Arc expression after ECS. We speculate that the decrease is caused by ECS-induced HDAC2 upregulation and decreased H3 acetylation at the Arc promoter.

Prostaglandin E2increases fibroblast gene‐specific and global DNA methylationviaincreased DNA methyltransferase expression

Although alterations in DNA methylation patterns have been associated with specific diseases and environmental exposures, the mediators and signaling pathways that direct these changes remain understudied. The bioactive lipid mediator prostaglandin E(2) (PGE(2)) has been shown to exert a myriad of effects on cell survival, proliferation, and differentiation. Here, we report that PGE(2) also signals to increase global DNA methylation and DNA methylation machinery in fibroblasts. HumanMethylation27 BeadChip array analysis of primary fetal (IMR-90) and adult lung fibroblasts identified multiple genes that were hypermethylated in response to PGE(2). PGE(2), compared with nontreated controls, increased expression and activity (EC(50)∼10(7) M) of one specific isoform of DNA methyltransferase, DNMT3a. Silencing of DNMT3a negated the ability of PGE(2) to increase DNMT activity. The increase in DNMT3a expression was mediated by PGE(2) signaling via its E prostanoid 2 receptor and the second messenger cAMP. PGE(2), compared with the untreated control, increased the expression and activity of Sp1 and Sp3 (EC(50)∼3×10(7) M), transcription factors known to increase DNMT3a expression, and inhibition of these transcription factors abrogated the PGE(2) increase of DNMT3a expression. These findings were specific to fibroblasts, as PGE(2) decreased DNMT1 and DNMT3a expression in RAW macrophages. Taken together, these findings establish that DNA methylation is regulated by a ubiquitous bioactive endogenous mediator. Given that PGE(2) biosynthesis is modulated by environmental toxins, various disease states, and commonly used pharmacological agents, these findings uncover a novel mechanism by which alterations in DNA methylation patterns may arise in association with disease and certain environmental exposures.