Effect of Folate on DNA in Colon Tissue and Blood Samples From Patients at Increased Risk of Developing Colorectal Neoplasia
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ABSTRACT:
DISEASE(S): Colon Cancer,Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2050314 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Background & Aims: Previous studies have suggested that dietary folic acid (FA) can protect against certain types of cancers. However, the findings have varied and the mechanisms by which this vitamin exerts chemopreventive effects remain to be clarified. We examined the effects of FA supplementation on DNA methylation, gene expression and gastric dysplasia in a transgenic mouse model that is etiologically and histologically well matched with human gastric cancers. Methods: Hypergastrinemic mice (INS-GAS) infected with Helicobacter felis were studied at multiple stages of gastric dysplasia and early cancer, with FA supplementation initiated both at weaning and later in life. Global DNA methylation was assessed by a methylation-sensitive cytosine incorporation assay, bisulfite pyrosequencing of B1 repetitive elements and immunohistochemistry (IHC) with anti-5-methylcytosine. We also profiled gene expression in the same tissues. Results: We found a decrease in global DNA methylation and tissue folate and an increase in serum homocysteine with progression of gastric dysplasia. FA supplementation prevented this loss of global DNA methylation and markedly reduced gastric dysplasia and mucosal inflammation. FA protected against the loss of global DNA methylation both in the dysplastic gastric epithelial cells and in gastric stromal myofibroblasts. In addition, FA supplementation had an anti-inflammatory effect, as indicated by expression profiling and IHC for lymphocyte markers. Conclusions: We conclude that FA supplementation is chemopreventive in this model of Helicobacter-associated gastric cancer. The beneficial effect of FA is likely due to its ability to reverse global loss of methylation and suppress inflammation. Study the difference in gene expression between transgenic hypergastrinemic (INS-GAS) mice fed a folate-supplemented diet and a diet with normal folate content. Because folate had a substantial protective effect, we matched the animals not only by folate status but also by dysplasia score (DYS). The degree of dysplasia was scored on a 1-4 scale. True replicates are not included. The first five samples are from folate supplemented animals, and the latter five are from controls on regular chow.
2011-07-20 | E-GEOD-30830 | biostudies-arrayexpress
Project description:We demonstrate that expression of key markers of keratinocyte differentiation is suppressed by exposure to sodium arsenite. Folate deficiency exacerbates this effect. In addition, cancer-related cell movement genes, and growth and proliferation genes are altered. Several redox-sensitive transcription factors are implicated in mediating these gene expression changes due to arsenic treatment and folate deficiency. Experiment Overall Design: K6/ODC mice were maintained on either a folate deficient or folate sufficient diet and exposed to 0, 1, or 10 ppm sodium arsenite in the drinking water for 30 days. Total RNA was isolated from skin samples and gene expression analyzed using Affymetrix Mouse 430 2.0 GeneChips. Data from 24 samples, with four mice in each of the six treatment groups, were analyzed.
2008-06-16 | E-GEOD-8733 | biostudies-arrayexpress
Project description:Periconceptual supplementation of women with folate is considered a great success for public health. Higher folate status, either by supplementation, or via the mandatory fortification of grain products in the United States, has lead to significant reduction in the incidence of neural tube defects. Besides birth defects, folate deficiency has been linked to a variety of morbidities, most notably to increased risk for cancer. However, recent evidence suggests that excess folate may be detrimental - for birth defect incidence or in the progression of cancer. How folate mediates beneficial or detrimental effects is not well understood. It is also unknown what molecular responses are elicited in women taking folate supplements, and thus experience a bolus of folate on top of the status achieved by fortification. To characterize this response, we performed gene expression profiling experiments on uterus tissue of pregnant mice after a preconceptional regimen of supplementation with folinic acid. We suggest that folinic acid supplementation affects expression of genes that contribute to protein synthesis and localization, genes that play a role for mitochondrial biology and oxidative phosphorylation, and genes encoding nucleotide-binding proteins, including protein kinases and GTP-binding intracellular signaling factors. The extent of such a response is strongly modulated by the genetic background. Finally, we suggest that folinic acid supplementation in this paradigm may affect histone methylation status, a potential avenue to mechanisms of gene regulation. Gene expression profiles were generated from uterus tissue. Female mice were either C57BL/6 wildtype, or homozygous for a Folr4 mutation, and received injections of either saline of folininc acid, respectively.
2013-03-31 | E-GEOD-36974 | biostudies-arrayexpress
Project description:Background: Consumption of high fat diets has negative impacts on health and well-being, some of which may be epigenetically regulated. Selenium and folate are two compounds which influence epigenetic mechanisms. We investigated the hypothesis that post-weaning supplementation with adequate levels of selenium and folate in mouse offspring fed a high fat, low selenium and folate diet during gestation and lactation will lead to epigenetic changes of potential importance for long-term health. Female offspring of mothers fed the experimental diet were either maintained on this diet (HF-low-low), or weaned onto a high-fat diet with sufficient levels of selenium and folate (HF-low-suf), for 8 weeks. Gene and protein expression, DNA methylation, and histone modifications were measured in colon and liver of female offspring. Results: Adequate levels of selenium and folate post-weaning affected gene expression in colon and liver of offspring, including decreasing Slc2a4 gene expression. Protein expression was only altered in the liver. There was no effect of adequate levels of selenium and folate on global histone modifications in the liver. Global liver DNA methylation was decreased in mice switched to adequate levels of selenium and folate, but there was no effect on methylation of specific CpG sites within the Slc2a4 gene in liver. Conclusions: Post-weaning supplementation with adequate levels of selenium and folate in female offspring of mice fed high-fat diets during gestation and lactation can alter global DNA methylation in liver. This may be one mechanism by which the negative effects of a poor diet during early life can be ameliorated. Further research is required to establish what role epigenetic changes play in mediating observed changes in gene and protein expression, and the relevance of these changes to health. Female wild type C57BL/6 mice (Animal Resource Centre, Western Australia) were fed a High Fat diet containing low levels of selenium and folate (HF-Low) for 7 days prior to mating with male C57BL/6 mice (Ruakura Small Animal Facility, Hamilton, New Zealand). Mothers were maintained on the HF-Low diet throughout gestation and lactation. Offspring of these female mice were randomly assigned to one of two different dietary treatments: either the same diet as the mothers (HF-Low), or a High Fat diet containing adequate selenium and folate (HF-Suf). At 12 weeks of age, mice were euthanized and colon and liver samples taken for microarray, proteomics, and DNA methylation analyses. Genomic DNA, total RNA and protein from whole colon and liver tissue was extracted using an AllPrepM-BM-. DNA/RNA/Protein mini kit (Qiagen, Cat number 80004). Colon and liver RNA from six female offspring on the HF-Low diet was compared with colon and liver RNA from six female offspring on the HF-Suf diet. All individual RNA samples were hybridized against a common reference RNA on separate arrays. The reference RNA was prepared by pooling in equimolar proportions RNA extracted from the intestine and liver of twelve female C57BL/6 mice, these being all of the mice from which samples were derived for microarray analysis in the current study.
2013-06-01 | E-GEOD-43038 | biostudies-arrayexpress
Project description:RATIONALE: Chemoprevention therapy is the use of certain agents to try to prevent the development of cancer. The use of folic acid may be effective in preventing colorectal cancer. Eating a diet rich in folic acid may prevent the development of colorectal cancer.
PURPOSE: This randomized phase I trial is studying how well a folate-depleted diet works compared to a folate-supplemented diet in preventing colorectal cancer in patients who are at high risk for developing colorectal cancer.
| 2011747 | ecrin-mdr-crc
Project description:Pediatric acute lymphoblastic leukemia (ALL) is believed to originate in utero and frequently involves aberrant promoter methylation. Folate is the methyl donor for DNA methylation, suggesting that maternal folate metabolism may contribute to the development of ALL. We previously reported significant associations between single nucleotide polymorphisms (SNPs) in the maternal methionine synthase (MTR) gene and offspring’s risk of ALL. Here, we test the associations of 11 SNPs in MTR with aberrant DNA methylation in offspring with ALL. We recruited 51 ALL case-mother pairs from Texas Children’s Hospital from 2005-2010. We collected maternal saliva samples and diagnostic bone marrow plasma from cases. Bone marrow plasma was obtained from six healthy donors. DNA methylation was determined using MCA-Seq. Pyrosequencing was used to determine maternal MTR genotypes. We identified offspring with high and low promoter methylation and used logistic regression to estimate the effects of maternal genotype on offspring methylation. Twenty-two cases (43%) demonstrated high promoter methylation. Maternal MTR 113A>G was associated with aberrant DNA methylation in offspring (OR 4.59, 95% CI 1.21-17.93). To the best of our knowledge, this is the first report of an association between maternal genotype and offspring methylation in pediatric ALL.
2018-05-03 | GSE99793 | GEO
Project description:Two maize inbred lines, DAN3130 and JI63, with different patterns of folate accumulation and different total folate contents in mature kernels were used to investigate the transcriptional regulation of folate metabolism during late stages of kernel formation by comparative transcriptome analysis; The fresh kernel samples of each inbred line were collected on DAP 24, DAP 35 days, respectively. Mature kernel samples were harvested after all the plants turned yellow. Three biological replicates of each sample were collected, and total RNA with high quality was pooled and sent for sequencing. Total RNA of high quality was pooled for transcriptome analysis, and raw RNA-seq data of DAP 24, DAP35 and mature kernels for both two inbred lines were obtained. The folate accumulation during DAP 24 to mature kernels could be controlled by circumjacent pathways of folate biosynthesis, such as pyruvate metabolism, glutamate metabolism and serine/glycine metabolism. In addition, the folate variation between these two inbred lines was related to those genes among folate metabolism, such as genes in the pteridine branch, ρ-ABA branch, serine/THF/5-M-THF cycle and the conversion of tetrahydrofolate monoglutamate to tetrahydrofolate polyglutamate; The findings provided insight into folate accumulation mechanisms during maize kernel formation to promote folate biofortification.
2022-04-19 | GSE195815 | GEO
Project description:Periconceptual supplementation of women with folate is considered a great success for public health. Higher folate status, either by supplementation, or via the mandatory fortification of grain products in the United States, has lead to significant reduction in the incidence of neural tube defects. Besides birth defects, folate deficiency has been linked to a variety of morbidities, most notably to increased risk for cancer. However, recent evidence suggests that excess folate may be detrimental - for birth defect incidence or in the progression of cancer. How folate mediates beneficial or detrimental effects is not well understood. It is also unknown what molecular responses are elicited in women taking folate supplements, and thus experience a bolus of folate on top of the status achieved by fortification. To characterize this response, we performed gene expression profiling experiments on uterus tissue of pregnant mice after a preconceptional regimen of supplementation with folinic acid. We suggest that folinic acid supplementation affects expression of genes that contribute to protein synthesis and localization, genes that play a role for mitochondrial biology and oxidative phosphorylation, and genes encoding nucleotide-binding proteins, including protein kinases and GTP-binding intracellular signaling factors. The extent of such a response is strongly modulated by the genetic background. Finally, we suggest that folinic acid supplementation in this paradigm may affect histone methylation status, a potential avenue to mechanisms of gene regulation.
2013-03-31 | GSE36974 | GEO
Project description:Rationale: Low B12 has been shown to play an important role in the prediction of metabolic risk, but its significance and mechanism in the development of adiposity and adipose tissue dysfunction is largely unknown. Objective: To investigate the role of B12 and folic acid in the development of adipocyte dysfunction. Methods and Results: Microarray analysis of human adipocytes (CHUB-S7 cell line) cultured and differentiated in customised media with varying concentrations of B12 and folic acid led to the identification of two important pathways: cholesterol synthesis and unfolded protein response (UPR). Adipocytes cultured in media with low B12 (150 pmol/L) or no B12 had increased intracellular total cholesterol, higher secreted homocysteine levels, induced UPR and reduced glucose uptake capacity compared to adipocytes cultured in normal media with higher B12. The folate concentrations had either no or little effect on the measured functions. Further analysis of these adipocytes for overall DNA methylation showed that the promoter regions of sterol regulatory element-binding transcription factor 1 (SREBF1) and low density lipoprotein receptor (LDLR) were hypomethylated in the low and no B12 conditions. The SREB proteins (SREBP1 and 2) and mRNA expressions (SREBF1 and LDLR) were also increased in the same conditions. Conclusion: The data suggest that low B12 can lead to adipocyte dysfunction by inducing excess cholesterol biosynthesis, homocysteine production and induction of UPR and overall adipocyte dysfunction. Both of these pathways and adipocyte dysfunction play a significant role in the development of cardiovascular diseases. Independent replicate samples of the human adipocyte cell line CHUB-S7 were treated with four different concentrations of B12 and folate.
2012-12-30 | E-GEOD-43166 | biostudies-arrayexpress
Project description:Folate deficiency causes widespread DNA breakages and is responsible for neural tube defect (NTD). However, little is known about the implications and mechanisms of these DNA instability to NTD. Here, by performing high-throughput sequencing, we generate genome-wide epigenetic profiles and map the distribution of DNA double-strands breaks (DSBs) in folate-antagonist treated embryonic stem cells. We find that DSBs exhibit distinct preference in active promoters and inhibit the interaction between enhancers and promoters. We uncover DSBs affected CTCF binding as a causal link for the abnormal expression of NTD susceptible genes. Finally, we propose a two-ways model for screening NTD susceptible genes and verifying 7 candidate genes in NTD fetuses with low folate level. In summary, our work demonstrate that folate deficiency induced DSBs trigger the dysregulation of NTD susceptible genes through impacting epigenetic regulation.
2020-05-01 | GSE149627 | GEO