Differential DNA methylation in experienced meditators after an intensive day of mindfulness-based practice: Implications for immune-related pathways.

The human methylome is dynamically influenced by psychological stress. However, its responsiveness to stress management remains underexplored. Meditation practice has been shown to significantly reduce stress level, among other beneficial neurophysiological outcomes. Here, we evaluated the impact of a day of intensive meditation practice (t2-t1 = 8 h) on the methylome of peripheral blood mononuclear cells in experienced meditators (n = 17). In parallel, we assessed the influence of a day of leisure activities in the same environment on the methylome of matched control subjects with no meditation experience (n = 17). DNA methylation profiles were analyzed using the Illumina 450 K beadchip array. We fitted for each methylation site a linear model for multi-level experiments which adjusts the variation between t1 and t2 for baseline differences. No significant baseline differences in methylation profiles was detected between groups. In the meditation group, we identified 61 differentially methylated sites (DMS) after the intervention. These DMS were enriched in genes mostly associated with immune cell metabolism and ageing and in binding sites for several transcription factors involved in immune response and inflammation, among other functions. In the control group, no significant change in methylation level was observed after the day of leisure activities. These results suggest that a short meditation intervention in trained subjects may rapidly influence the epigenome at sites of potential relevance for immune function and provide a better understanding of the dynamics of the human methylome over short time windows.

Vitamin D deficiency during pregnancy affects the function of Th1/Th2 cells and methylation of IFN-γ gene in offspring rats.

The effects of maternal vitamin D status on offspring's Th1/Th2 cell function and the related mechanisms have not been reported. In this study, we established the rat model of vitamin D deficiency during pregnancy. 48 female Sprague-Dawley rats (8 weeks old) were randomly assigned to three groups (n = 16/group): control group (fed with standard AIN-93 G diet until parturition), vitamin D deficiency group (VDD group, fed with vitamin D deficient diet until parturition) and vitamin D supplementation group (VDS group, fed with vitamin D deficient diet prior to mating and with standard AIN-93 G diet during pregnancy). At 4 weeks of age, the ratio of T helper type 1/ T helper type 2 (Th1/Th2) cells and the levels of Th1/Th2 cytokines (IFN-γ, IL-4, IL-5, IL-6, IL-10 and IL-13) in offspring rats were determined by Flow Cytometry and Meso Scale Discovery, respectively. Furthermore, DNA methyltransferase (DNMT) activity as well as the methylation levels of IFN-γ and IL-4 genes were measured. As a result, rats in the VDD group showed a significant decrease in Th1/Th2 ratio and IFN-γ level and an increase in IL-4 level. Additionally, up-regulated DNMT activity and increased methylation rate of IFN-γ gene was shown in VDD offspring rats. Supplementation with vitamin D during pregnancy reversed the above abnormalities. In conclusion, maternal vitamin D deficiency affected the function of Th1/Th2 cells and methylation of IFN-γ gene in offspring rats. Meanwhile, maternal vitamin D deficiency had the potential to regulate DNMT activity, which may determine the status of methylation.

Improving cancer immunotherapy with DNA methyltransferase inhibitors.

Immunotherapy confers durable clinical benefit to melanoma, lung, and kidney cancer patients. Challengingly, most other solid tumors, including ovarian carcinoma, are not particularly responsive to immunotherapy, so combination with a complementary therapy may be beneficial. Recent findings suggest that epigenetic modifying drugs can prime antitumor immunity by increasing expression of tumor-associated antigens, chemokines, and activating ligands by cancer cells as well as cytokines by immune cells. This review, drawing from both preclinical and clinical data, describes some of the mechanisms of action that enable DNA methyltransferase inhibitors to facilitate the establishment of antitumor immunity.

Prenatal maternal immune activation causes epigenetic differences in adolescent mouse brain.

Epigenetic processes such as DNA methylation have been implicated in the pathophysiology of neurodevelopmental disorders including schizophrenia and autism. Epigenetic changes can be induced by environmental exposures such as inflammation. Here we tested the hypothesis that prenatal inflammation, a recognized risk factor for schizophrenia and related neurodevelopmental conditions, alters DNA methylation in key brain regions linked to schizophrenia, namely the dopamine rich striatum and endocrine regulatory centre, the hypothalamus. DNA methylation across highly repetitive elements (long interspersed element 1 (LINE1) and intracisternal A-particles (IAPs)) were used to proxy global DNA methylation. We also investigated the Mecp2 gene because it regulates transcription of LINE1 and has a known association with neurodevelopmental disorders. Brain tissue was harvested from 6 week old offspring of mice exposed to the viral analog PolyI:C or saline on gestation day 9. We used Sequenom EpiTYPER assay to quantitatively analyze differences in DNA methylation at IAPs, LINE1 elements and the promoter region of Mecp2. In the hypothalamus, prenatal exposure to PolyI:C caused significant global DNA hypomethylation (t=2.44, P=0.019, PolyI:C mean 69.67%, saline mean 70.19%), especially in females, and significant hypomethylation of the promoter region of Mecp2, (t=3.32, P=0.002; PolyI:C mean 26.57%, saline mean 34.63%). IAP methylation was unaltered. DNA methylation in the striatum was not significantly altered. This study provides the first experimental evidence that exposure to inflammation during prenatal life is associated with epigenetic changes, including Mecp2 promoter hypomethylation. This suggests that environmental and genetic risk factors associated with neurodevelopmental disorders may act upon similar pathways. This is important because epigenetic changes are potentially modifiable and their investigation may open new avenues for treatment.