Environment, diet and CpG island methylation: epigenetic signals in gastrointestinal neoplasia.
ABSTRACT The epithelial surfaces of the mammalian alimentary tract are characterised by very high rates of cell proliferation and DNA synthesis, and in humans they are highly susceptible to cancer. The role of somatic mutations as drivers of carcinogenesis in the alimentary tract is well established, but the importance of gene silencing by epigenetic mechanisms is increasingly recognised. Methylation of CpG islands is an important component of the epigenetic code that regulates gene expression during development and normal cellular differentiation, and a number of genes are well known to become abnormally methylated during the development of tumours of the oesophagus, stomach and colorectum. Aberrant patterns of DNA methylation develop as a result of pathological processes such as chronic inflammation, and in response to various dietary factors, including imbalances in the supply of methyl donors, particularly folates, and exposure to DNA methyltransferase inhibitors, which include polyphenols and possibly isothiocyanates from plant foods. However the importance of these environmental interactions in human health and disease remains to be established. Recent moves to modify the exposure of human populations to folate, by mandatory supplementation of cereal foods, emphasise the importance of understanding the susceptibility of the human epigenome to dietary and other environmental effects.
SourceAvailable from: Ana Laura de la Garza[Show abstract] [Hide abstract]
ABSTRACT: Type-2 diabetes is associated with a chronic low-grade systemic inflammation accompanied by an increased production of adipokines/cytokines by obese adipose tissue. The search for new antidiabetic drugs with different mechanisms of action, such as insulin sensitizers, insulin secretagogues and α-glucosidase inhibitors, has directed the focus on the potential use of flavonoids in the management of type-2 diabetes. Thirty six diabetic male C57BL/6J db/db mice were fed a standard diet and randomly assigned into four experimental groups: non-treated control, (n = 8); acarbose (5 mg per kg bw, n = 8); helichrysum (1 g per kg bw, n = 10) and grapefruit (0.5 g per kg bw, n = 10) for 6 weeks. The mRNA expression in pancreas, liver and epididymal adipose tissue was determined by RT-PCR. DNA methylation was quantified in epididymal fat using pyrosequencing. Mice supplemented with helichrysum and grapefruit extracts showed a significant decrease in fasting glucose levels (p < 0.05). A possible mechanism of action could be the up-regulation of liver glucokinase (p < 0.05). The antihyperglycemic effect of both extracts was accompanied by decreased mRNA expression of some proinflammatory genes (monocyte chemotactic protein-1, tumor necrosis factor-α, cyclooxygenase-2, nuclear factor-kappaB) in the liver and epididymal adipose tissue. The CpG3 site of TNFα, located 5 bp downstream of the transcription start site, showed increased DNA methylation in the grapefruit group compared with the non-treated group (p < 0.01). In conclusion, helichrysum and grapefruit extracts improved hyperglycemia through the regulation of glucose metabolism in the liver and reduction of the expression of proinflammatory genes in the liver and visceral fat. The hypermethylation of TNFα in adipose tissue may contribute to reduce the inflammation associated with diabetes and obesity.Food & Function 07/2014; 5(9). DOI:10.1039/c4fo00154k · 2.91 Impact Factor
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ABSTRACT: The colorectal mucosal epithelium is composed of rapidly proliferating crypt cells derived by clonal expansion from stem cells. The aging human colorectal mucosa develops aberrant patterns of DNA methylation that may contribute to its increasing vulnerability to cancer. Various types of evidence suggest that age-dependent loss of global methylation, together with hypermethylation of CpG islands associated with cancer-related genes, may be influenced by nutritional and metabolic factors. Folates are essential for the maintenance of normal DNA methylation, and folate metabolism is known to modify epigenetic mechanisms under experimental conditions. Human intervention trials and cross-sectional studies suggest a role for folates and other nutritional and metabolic factors as determinants of colorectal mucosal DNA methylation. Future studies should focus on the possibility that folic acid fortification may exert unforeseen effects on the human gastrointestinal epigenome. Naturally occurring DNA methyltransferase inhibitors in plant foods may be useful for the manipulation of epigenetic profiles in health and disease.Epigenomics 04/2014; 6(2):239-51. DOI:10.2217/epi.14.8 · 2.43 Impact Factor
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ABSTRACT: Detecting aberrant DNA methylation as diagnostic or prognostic biomarkers for cancer has been a topic of considerable interest recently. However, current classifiers based on absolute methylation values detected from a cohort of samples are typically difficult to be transferable to other cohorts of samples. Here, focusing on relative methylation levels, we employed a modified rank-based method to extract reversal pairs of CpG sites whose relative methylation level orderings differ between disease samples and normal controls for cancer diagnosis. The reversal pairs identified for five cancer types respectively show excellent prediction performance with the accuracy above 95%. Furthermore, when evaluating the reversal pairs identified for one cancer type in an independent cohorts of samples, we found that they could distinguish different subtypes of this cancer or different malignant stages including early stage of this cancer from normal controls. The identified reversal pairs also appear to be specific to cancer type. In conclusion, the reversal pairs detected by the rank-based method could be used for accurate cancer diagnosis, which are transferable to independent cohorts of samples. Copyright © 2014 Elsevier B.V. All rights reserved.Gene 11/2014; 555(2). DOI:10.1016/j.gene.2014.11.004 · 2.20 Impact Factor