Irreversible global DNA hypomethylation as a key step in hepatocarcinogenesis induced by dietary methyl deficiency

Pogribny, Igor P.; Ross, Sharon A.; Wise, Carolyn; Pogribna, Marta; Jones, Elisabeth A.; Tryndyak, Volodymyr; James, S. Jill; Dragan, Yvonne P.; Poirier, Lionel A.

doi:10.1016/j.mrfmmm.2005.06.028

Cited by 165 publications

(106 citation statements)

References 32 publications

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“…In this respect it is worth emphasizing that nutrient restriction was within physiological ranges encountered in both sheep and humans (5-7) and that animals exhibited no signs of clinical deficiency. Importantly, key components of the methionine cycle within the ovarian follicle were altered, including the ratio of SAM to SAH, which is associated with the extent of DNA methylation (16).…”

Section: Discussionmentioning

confidence: 99%

DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status

Sinclair

Allegrucci

Singh

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

714

559

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A complex combination of adult health-related disorders can originate from developmental events that occur in utero. The periconceptional period may also be programmable. We report on the effects of restricting the supply of specific B vitamins (i.e., B12 and folate) and methionine, within normal physiological ranges, from the periconceptional diet of mature female sheep. We hypothesized this would lead to epigenetic modifications to DNA methylation in the preovulatory oocyte and/or preimplantation embryo, with long-term health implications for offspring. DNA methylation is a key epigenetic contributor to maintenance of gene silencing that relies on a dietary supply of methyl groups. We observed no effects on pregnancy establishment or birth weight, but this modest early dietary intervention led to adult offspring that were both heavier and fatter, elicited altered immune responses to antigenic challenge, were insulin-resistant, and had elevated blood pressure-effects that were most obvious in males. The altered methylation status of 4% of 1,400 CpG islands examined by restriction landmark genome scanning in the fetal liver revealed compelling evidence of a widespread epigenetic mechanism associated with this nutritionally programmed effect. Intriguingly, more than half of the affected loci were specific to males. The data provide the first evidence that clinically relevant reductions in specific dietary inputs to the methionine/folate cycles during the periconceptional period can lead to widespread epigenetic alterations to DNA methylation in offspring, and modify adult healthrelated phenotypes. E vidence from both epidemiological studies in humans and direct intervention studies in animals indicates that altering key developmental processes in utero can predispose offspring to many late-onset diseases such as dyslipidemia, type II diabetes, and heart disease (1, 2). In this regard, the effects of gross nutrient or protein deficiencies in maternal diet during pregnancy are well documented (3), although little is known about the effects of specific nutrients or the timing and mechanistic basis of nutrient programming (4). Here we investigated the effects of restricting the supply of specific B group vitamins (i.e., vitamin B 12 and folate) and sulfur amino acids (in particular, methionine) from the diet of adult female sheep from 8 weeks preceding until 6 days after conception, within physiological ranges encountered in both sheep (5) and humans (i.e., within the 5th and 95th percentiles) (6, 7). These micronutrients are important intermediates and/or have specific regulatory functions in the linked methionine-folate cycles (5, 7). In rodents, maternal supraphysiological methyl group supply and a low-protein diet (50% control) offered throughout pregnancy altered DNA methylation of candidate genes (agouti, glucocorticoid receptor, and peroxisomal proliferator-activated receptor-␣) (8, 9), but the extent of methylation change in these or more clinically relevant diets is not known. Gametes and preimplantation emb...

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Section: Discussionmentioning

confidence: 99%

DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status

Sinclair

Allegrucci

Singh

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

714

559

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“…10 Stable DNA hypomethylation in tissue that undergoes carcinogenesis is also related to cancer progression from normal to tumor cell. 11 Although it is not yet well understood why all cancer tissue does not undergo hypomethylation in the same manner, human cancers can be classified into two groups: a low (0-3.4%) hypomethylation group; and a moderately high (6.8-9.5%) hypomethylation group. 12 Global hypomethylation is a very early event in human and experimental carcinogenesis and a feature of genomic DNA derived from solid and hematologic tumors,…”

Section: Introductionmentioning

confidence: 99%

Global DNA Hypomethylation in Liver Cancer Cases and Controls: A Phase I Preclinical Biomarker Development Study

Guerrero-Preston

Santella²,

Blanco³

et al. 2007

Epigenetics

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Key woRDSglobal genomic hypomethylation, epigenetics of hepatocarcinogenesis, epigenetic biomarkers for early detection, molecular cancer screening technology, epigenetic approaches to cancer epidemiology ABStRActBackground: Global genomic DNA hypomethylation is a feature of genomic DNA derived from solid and hematologic tumors in animal models and human carcinogenesis. Global genomic DNA hypomethylation may be the earliest epigenetic change from a normal to a pre-malignant cell.Objectives: To test if global hypomethylation is a good marker for early detection of cancer we used a novel quantification method of 2'-deoxynucleosides to evaluate DNA methylation in liver cancer cases and controls.Methods: Frozen tissue from liver cancer patients and controls were obtained from the Cooperative Human Tissue Network. DNA was extracted using standard methods. Genomic DNA samples were boiled and treated with nuclease P1 and alkaline phosphatase. Global genomic DNA methylation patterns were obtained using HPLC for fraction separation and mass spectrometry for quantification. A two-sample t-test was performed using Welch's approximation for samples with unequal variances. A Wilcoxon rank sum test was also performed.Results: A global genomic DNA methylation index measuring methylated cytidine relative to global cytidine in the genome was significantly lower (p value = 0.001) for all cases, mean = 2.43 (95% CI, 2.08, 2.78), when compared to controls, mean = 3.55 (95% CI, 3.16, 3.93).Discussion: A correlation between global genomic DNA methylation patterns and type of liver tissue was observed. These results add to the accumulating body of evidence suggesting that global DNA hypomethylation may be a useful biomarker to distinguish between liver cancer cases and controls.

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“…Their data revealed a global DNA hypomethylation in mice from all time frames, even though rats treated with the folate deficient diet for the shortest amount of time (9 weeks) were found to revert back to normal DNA methylation patterns after their return to the sufficient diet. For all other groups, the folate deficient diet led to long term changes to their DNA methylation patterns (Pogribny et al, 2006). It can be thus argued that since the 8-week period of methyl-deficiency analyzed in this study was considerably shorter than that in the Pogribny study, which could potentially explain the negative findings.…”

Section: Effects Of Methyl-donor Deficiency On Estr Mutation Inductionmentioning

confidence: 59%

“…It is known that depletion of any one of the major dietary sources of methyl groups (methionine, choline, folic acid and vitamin B 12 ) is enough to induce tumor formation in rat and mice models. As stated by Pogribny and co-authors, the methyl-deficient model of endogenous carcinogenesis is unique in the fact that dietary omission rather than the addition of chemical carcinogens leads to the formation of tumors (Pogribny et al, 2006). Predisposition to cancer by dietary omission is caused by biochemical and molecular events leading to chronic metabolic stress thus in vivo models could be ideal in studying progressive alterations that occur at the duration of carcinogenic progress (Pogribny et al, 2006).…”

Section: Cancer Riskmentioning

confidence: 99%

“…Contradicting data from the Pogribny group showed prolonged DNA hypomethylation after a subjection of folate deficient diet in rodents (Pogribny et al, 2006). A study by McKay and coauthors examined the effects of low-folate diet on murine offspring exposed during gestation and lactation, and showed a decrease in global methylation status in the small intestinal tissue of the adult mice (McKay et al, 2011a).…”

Section: 21)mentioning

confidence: 99%

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The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice

Voutounou

Glen

Dubrova

2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Irreversible global DNA hypomethylation as a key step in hepatocarcinogenesis induced by dietary methyl deficiency

Cited by 165 publications

References 32 publications

DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status

DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status

Global DNA Hypomethylation in Liver Cancer Cases and Controls: A Phase I Preclinical Biomarker Development Study

The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice

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