BackgroundOxidative stress may lead to an increased level of unrepaired cellular DNA damage, which is discussed as one risk for tumor initiation. Mismatch repair (MMR) enzymes act as proofreading complexes that maintain the genomic integrity and MMR-deficient cells show an increased mutation rate. One important gene in the MMR complex is the MutL homolog 1 (MLH1) gene. Since a diet rich in antioxidants has the potential to counteract harmful effects by reactive oxygen species (ROS), we investigated the impact of an antioxidant, folate, and vitamin rich diet on the epigenetic pattern of MLH1. These effects were analyzed in individuals with non-insulin depended diabetes mellitus type 2 (NIDDM2) and impaired fasting glucose (IFG).MethodsIn this post-hoc analysis of a randomized trial we analyzed DNA methylation of MLH1, MSH2, and MGMT at baseline and after 8 weeks of intervention, consisting of 300 g vegetables and 25 ml plant oil rich in polyunsaturated fatty acids per day. DNA methylation was quantified using combined bisulfite restriction enzyme analysis (COBRA) and pyrosequencing. MLH1 and DNMT1 mRNA expression were investigated by qRT-PCR. DNA damage was assessed by COMET assay. Student’s two-tailed paired t test and one-way ANOVA with Scheffé corrected Post hoc test was used to determine significant methylation and expression differences. Two-tailed Pearson test was used to determine correlations between methylation level, gene expression, and DNA strand break amount.ResultsThe intervention resulted in significantly higher CpG methylation in two particular MLH1 promoter regions and the MGMT promoter. DNA strand breaks and methylation levels correlated significantly. The expression of MLH1, DNMT1, and the promoter methylation of MSH2 remained stable. CpG methylation levels and gene expression did not correlate.ConclusionThis vitamin and antioxidant rich diet affected the CpG methylation of MLH1. The higher methylation might be a result of the ROS scavenging antioxidant rich diet, leading to lower activity of DNA demethylating enzymes. Our results suggest the hypothesis of CpG demethylation via DNA repair enzymes under these circumstances. NIDDM2 and IFG patients benefit from this simple dietary intervention involving epigenetic and DNA repair mechanisms.

Background: The tumor suppressor genes p15^INK4b and p16^INK4a as well as the estrogen receptor-α (ESR1) gene are abnormally methylated and expressed in colon cancer. The cancer-preventative abilities of several bioactive food components have been linked to their estrogenic and epigenetic activities. Methods: The effect of folic acid, zebularine, resveratrol, genistein and epigallocatechin-3-gallate (EGCG) on tumor cell growth, promoter methylation of ESR1, p15^INK4b and p16^INK4a and gene expression of ESR1 and ESR2 was analyzed in Caco-2 cells. Gene expression was measured using real-time PCR, and promoter CpG methylation was assessed using bisulfite conversion and methylation-specific PCR. Results: After exposure to a high concentration of folic acid (20 µmol/l), enhanced cancer cell growth and concomitant increased methylation of the ESR1 (3.6-fold), p16^INK4a and p15^INK4b promoters was observed. A lower concentration of folic acid (2 µmol/l) decreased cell growth. The phytoestrogens genistein and resveratrol enhanced expression of ESR1 (genistein 200 µmol/l: 2.1-fold; resveratrol 50 µmol/l: 6.3-fold) and ESR2 (2.6- and 3.6-fold, respectively). Genistein and resveratrol treatment increased promoter methylation of ESR1 (genistein 200 µmol/l: 2.9-fold; resveratrol 50 µmol/l: 1.4-fold). For p16^INK4a, increased methylation was found after exposure to 10 µmol/l resveratrol, but for p15^INK4b, decreased methylation was found. Both components showed growth-inhibitory activities. For EGCG, growth inhibition at 100 µmol/l and suppressed promoter methylation of tumor suppressor genes (p16^INK4a: 0.9-fold; p15^INK4b: 0.6-fold) was seen. Conclusions: Our results show that these food compounds regulate ESR and tumor suppressor gene expression by multiple mechanisms including epigenetic processes. An improved understanding of these epigenetic effects could therefore support specific dietary concepts of epigenetic cancer prevention and intervention.

Introduction: Obesity is a multifactorial condition that results from the interactions among genetic, dietary, environmental, and lifestyle factors. In our study, we have employed a novel integrative approach to identify mechanisms involved in human disease. Method: In contrast to previous methodologies employed for integration of heterogeneous OMIC data, we based the integration on genomic positions of alterations in human disease. A data search for various types of studies on obesity (genome-wide association, meta-analysis, transcriptomic, proteomic studies and epigenetic studies) was conducted in literature sources and OMIC data repositories, using GWAS Central and Medline database with search string (obesity) AND (transcriptome OR proteome OR genome-wide OR microarray OR profiling OR epigenetics). Additionally, Gene Expression Omnibus (GEO) repository, Array Express and Stanford Microarray Database were searched to discover suitable sources of data for inclusion in our initial dataset. Results and Discussion: As a result of the employed high through put technology, 71 high scoring regions were identified. We identified 8 high scoring gene regions (ATP5O, ALK7, CR1, CR2, S100, GAPDH, TLR1 and TLR6) that have not yet been associated to obesity. Interestingly, all of these genes were identified by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes to be implicated in the energy metabolism and the immune response, which are known to be involved in obesity. Conclusion: In our study, we have performed a novel integrative approach to identify candidate regions and genes involved in human disease. The results showed that none of the high scoring genes that were identified were yet associated with obesity per se, but that they were found to be implicated in the immune response or the energy metabolism. Further research will be needed to validate the found gene regions for obesity.

Background: In recent years, more and more evidence has accumulated to elucidate the modulating roles of microRNA in immune and inflammatory system. We conducted a novel positional omics integration study to identify microRNAs that could shed further light on the possible links between microRNAs, adipose tissue immunity/inflammation and obesity.

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