Helge Frieling

Lowered DNA methyltransferase (DNMT-3b) mRNA expression is associated with genomic DNA hypermethylation in patients with chronic alcoholism

Summary.DNA methyltransferases (DNMTs) are involved within the epigenetic control of DNA methylation processes. Recently, it has been shown that the genomic DNA methylation in patients with alcoholism is increased. In the present controlled study we observed a significant decrease of mRNA expression of DNMT-3a and DNMT-3b when comparing alcoholic patients (n = 59) with healthy controls (n = 66): DNMT-3a (t = −2.38, p = 0.019), DNMT-3b (t = −2.65, p = 0.008). No significant differences were seen for DNMT-1 and Mbd-2 (Methyl-CpG-Binding-Domain protein 2) expression. Additionally, we observed a significant negative correlation between DNMT-3b expression and the blood alcohol concentration (r = −0.45, p = 0.003) which might explain the decrease of DNMT-3b mRNA expression in alcoholic patients. Using a multivariate model we observed that the increase (10%) of genomic DNA methylation in patients with alcoholism was significantly associated with their lowered DNMT-3b mRNA expression (multiple linear regression, p = 0.014). Since methylation of DNA is an important epigenetic factor in regulation of gene expression these findings may have important implications for a possible subsequent derangement of epigenetic control in these patients.

Epigenetic dysregulation of dopaminergic genes in eating disorders

OBJECTIVE The pathophysiology of eating disorders such as anorexia nervosa (AN) and bulimia nervosa (BN) has been linked to an impaired dopaminergic neurotransmission, still the origin of this disturbance remains unknown. The aim of the present study was, therefore, to evaluate whether the expression of dopaminergic genes is altered in the blood of patients suffering from eating disorders and if these alterations can be explained by changes in the promoter specific DNA methylation of the genes. METHOD We used quantitative real-time PCR to measure both the expression and the promoter specific DNA methylation of the dopamine transporter (DAT), and the D2 (DRD2) and D4 receptor (DRD4) gene in the blood of 46 patients (22 AN, 24 BN) and 30 healthy controls. RESULTS Patients showed an elevated expression of DAT mRNA when compared with the controls and a downregulation of the DRD₂ expression. The upregulation of the DAT gene was accompanied by a hypermethylation of the genes promoter in the AN and BN group while a significant hypermethylation of the DRD₂ promoter was only present in the AN group. No differences in expression or methylation were found for the other dopamine receptors investigated. DISCUSSION Our study shows a disturbed expression of dopaminergic genes that is accompanied by a dysregulation of the epigenetic DNA methylation. Further studies are necessary to provide more insight into the epigenetic dysregulation of the dopaminergic neurotransmission in the pathophysiology of eating disorders.

Promoter specific methylation of the dopamine transporter gene is altered in alcohol dependence and associated with craving

Dopaminergic neurotransmission plays a crucial role in the genesis and maintenance of alcohol dependence. Epigenetic regulation via promoter specific DNA methylation of the dopamine transporter gene (DAT) may influence altered dopaminergic neurotransmission in alcoholism. Aim of the present study was to investigate DNA promoter methylation of DAT in early alcohol withdrawal and in relation to alcohol craving. We analyzed blood samples of 76 patients admitted for detoxification treatment and compared them to 35 healthy controls. Methylation specific quantitative real-time PCR was used to measure the promoter specific DNA methylation of the dopamine transporter. We assessed the extent of alcohol craving using the obsessive compulsive drinking scale (OCDS). Compared to healthy controls we found a significant hypermethylation of the DAT-promoter (Mann-Whitney U-test: p=0.001). Ln-transformed methylation of the DAT-promoter was negatively associated with the OCDS (linear regression: Beta=-0.275, p=0.016), particularly with the obsessive subscale (Beta=-0.300, p=0.008). Findings of the present study show that the epigenetic regulation of the DAT-promoter is altered in patients undergoing alcohol withdrawal. Furthermore, hypermethylation of the DAT-promoter may play an important role in dopaminergic neurotransmission and is associated with decreased alcohol craving.

Promoter specific DNA methylation and gene expression of POMC in acutely underweight and recovered patients with anorexia nervosa

Proopiomelanocortin (POMC) and its derived peptides, in particular alpha-MSH, have been shown to play a crucial role in the regulation of hunger, satiety and energy homeostasis. Studies in patients with anorexia nervosa (AN) suggest an abnormal expression of appetite-regulating hormones. Hormone expression levels may be modulated by epigenetic mechanisms, which were recently shown to be implicated in the pathophysiology of eating disorders. We hypothesised that POMC promoter specific DNA methylation and gene expression will be affected by malnutrition and therefore differ in AN patients at distinct stages of the disorder. Promoter specific DNA methylation of the POMC gene and expression of POMC mRNA variants were determined in peripheral blood mononuclear cells (PBMC) of 30 healthy control women (HCW), 31 underweight (acAN) and 30 weight-recovered patients with AN (recAN). Malnutrition was characterized by plasma leptin. Expression of the functionally relevant long POMC mRNA transcript was significantly correlated with leptin levels and higher in acAN compared to recAN and HCW. Expression of the truncated form and mean promoter DNA methylation was similar in all three subgroups. Methylation of single CpG residues in the E2F binding site was inversely related to POMC expression. Our preliminary data on pattern of POMC regulation suggests an association with the underweight state rather than with persisting trait markers of AN. In contrast to POMC expression in the central nervous system, peripheral POMC mRNA expression decreased with malnutrition and hypoleptinemia. This may represent a counterregulatory mechanism as part of the crosstalk between the immune and neuroendocrine systems.

Blue light improves cognitive performance

SummaryA newly discovered system of photoreceptors for circadian rhythms works non-visual and responds to blue light (460 nm). We report a longitudinal study in 44 adults, showing that a significant increase in alertness and speed of information processing could be achieved by blue light as compared to normal light.

Epigenetics and depression: current challenges and new therapeutic options.

Purpose of review Epigenetics comprises heritable but concurrent variable modifications of genomic DNA defining gene expression. The aim of this publication is to review the field of epigenetics in depression. Within this scope, we outline potential therapeutic options evolving in this young field of psychiatric research. Recent findings Recently published papers show that epigenetic mechanisms like histone modifications and DNA methylation affect diverse pathways leading to depression-like behaviors in animal models. Adverse alterations of gene expression profiles, including glucocorticoid receptor or brain-derived neurotrophic factor, were shown to be inducible by early life stress and reversible by epigenetic drugs. Postmortem studies revealed epigenetic changes in the frontal cortex of depressed suicide victims. There exists profound evidence for histone deacetylase inhibitors to be a novel line of effective antidepressants via counteracting previously acquired adverse epigenetic marks. Summary Because of the complex causal factors leading to depression, epigenetics is of considerable interest for the understanding of early life stress in depression. The current research regarding epigenetic pharmaceuticals is promising and deserves further attention in depression and psychiatry in general, and may strike out new ways towards individually tailored therapies.

Global DNA hypomethylation and DNA hypermethylation of the alpha synuclein promoter in females with anorexia nervosa

Global DNA hypomethylation and DNA hypermethylation of the alpha synuclein promoter in females with anorexia nervosa

Methylation of the promoter of brain-derived neurotrophic factor exon IV and antidepressant response in major depression

Methylation of the promoter of brain-derived neurotrophic factor exon IV and antidepressant response in major depression

DNA methylation of the POMC gene promoter is associated with craving in alcohol dependence

Hypothalamic–pituitary–adrenal (HPA) axis dysfunction has been implicated in the pathogenesis of addictive behaviour and especially in alcohol craving. The pro-opiomelanocortin gene (POMC), encoding a 241 amino acids stretching polypeptide hormone precursor, plays an important role in the regulation of the HPA, and is prone to epigenetic regulation due to promoter-related DNA methylation. Aim of the present study therefore was to investigate possible differences in promoter-related DNA methylation in patients suffering from alcohol dependence compared to healthy controls. We analysed the DNA methylation of the 5′ promoter of the POMC gene that is embedded in a CpG island using bisulfite sequencing in 145 alcohol-dependent patients and 37 healthy controls taken from the Franconian Alcoholism Research Studies. We found only marginal, hence significant differences at single CpG sites between patients and controls. We identified a cluster of CpGs showing a significant association with alcohol craving in the patients group. These results implicate that epigenetic changes possibly due to alcohol intake may contribute to craving via promoting HPA-axis dysfunction. Further studies should more closely investigate the impact of these changes on the several derivatives of the POMC gene.

Global DNA methylation is influenced by smoking behaviour

The level of epigenetic DNA methylation is an important factor in the pathogenesis of various human diseases. As smoking may influence DNA methylation, we investigated the effect of smoking habits on global DNA methylation in 298 genomic DNA samples (73 fathers, 69 mothers and 156 offspring). We did not find a direct effect of smoking on global DNA methylation. However, there was an association of the offsprings DNA methylation with paternal DNA methylation that was strongest if both had never smoked (R2corr=0.41, Beta=0.68, p=0.02) and completely vanished if the offspring smoked or had ever smoked. These findings suggest an association between smoking behaviour and global DNA methylation, which may be of importance for a wide range of diseases.