Genomic DNA methylation decreases in response to moderate folate depletion in elderly women

Rampersaud, Gail C.; Kauwell, Gail P. A.; Hutson, Alan D.; Cerda, James J.; Bailey, Lynn B.

doi:10.1093/ajcn/72.4.998

Cited by 338 publications

(240 citation statements)

References 20 publications

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“…Consistent with this notion, resting lymphocytes have been shown to turnover SAM at a rate 3-5 times higher than that estimated for most nonhepatic tissues (68). Further, lymphocyte DNA hypomethylation was recently documented in women undergoing controlled folate depletion (69,70). Taken together, these observations suggest that global hypomethylation in lymphocyte DNA may be an early biomarker of abnormal methylation in other tissues.…”

Section: Discussionmentioning

confidence: 64%

Increase in Plasma Homocysteine Associated with Parallel Increases in Plasma S-Adenosylhomocysteine and Lymphocyte DNA Hypomethylation

Melnyk

Pogribna

et al. 2000

Journal of Biological Chemistry

586

381

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An elevation in plasma homocysteine is a sensitive but nonspecific biomarker for an imbalance in the integrated pathways of one-carbon metabolism (1, 2). Chronic nutritional deficiencies in folate, choline, methionine, vitamin B 6 , and/or vitamin B 12 can perturb the complex regulatory network that maintains normal one-carbon metabolism and homocysteine homeostasis (3-7). Genetic polymorphisms in these pathways can act synergistically with nutritional deficiencies to accelerate the metabolic pathology associated with chronic disease states (8). Although several hypotheses have been proposed to explain the association between hyperhomocysteinemia and the thrombotic/atherosclerotic process occurring with occlusive cardiovascular disease, as yet none has been definitive (9 -12). Similarly, increases in plasma homocysteine concentrations have been associated with increased risk of certain birth defects (13-16), but the underlying mechanism remains elusive. A major unanswered question is whether direct cellular toxicity of homocysteine is causally involved in pathogenesis or whether homocysteinemia is simply a passive and indirect indicator of a more complex mechanism.Homocysteine is derived solely from methionine metabolism and is significantly recycled to conserve sufficient methionine for protein and S-adenosylmethionine synthesis. The interactive and interdependent pathways of the methionine/homocysteine cycle are diagrammed in Fig. 1 to emphasize the indirect effects of pathway perturbations on cellular methyltransferase reactions. The metabolic generation of homocysteine from methionine is initiated by the ATP-dependent transfer of adenosine to methionine via methionine adenosyltransferase. The product, S-adenosylmethionine (SAM), 1 is a priority for onecarbon metabolism because it is the methyl donor for most cellular methyltransferase reactions. In addition to DNA methylation, SAM-dependent methyltransferase activity is essential for hundreds of other cellular methylation reactions including synthesis of creatine in the liver, membrane phosphatidylcholine synthesis, central nervous system neurotransmittor synthesis, methylation/detoxification, and RNA and protein methylation (17). After transfer of the methyl group, SAM is converted to S-adenosylhomocysteine (SAH) within the active site of the methyltransferase enzyme. Because most methyltransferases bind SAH with higher affinity than SAM, they are subject to potent product inhibition by SAH (18). Thus, the efficiency of methyltransferase reactions is absolutely dependent on efficient product removal of SAH. This is effectively accomplished by SAH hydrolase (SAHH), an enzyme that appears to act in close proximity to the methyltransferases, at least in the nucleus (19). The crystal structure of SAHH has been recently reported, and interestingly, the polypeptide folding pattern at the catalytic domain of SAHH is almost identical to that reported for the DNA methyltransferases and suggests that SAH molecules can travel easily between the catalytic pockets of th...

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Section: Discussionmentioning

confidence: 64%

Increase in Plasma Homocysteine Associated with Parallel Increases in Plasma S-Adenosylhomocysteine and Lymphocyte DNA Hypomethylation

Melnyk

Pogribna

et al. 2000

Journal of Biological Chemistry

586

381

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show abstract

“…49 Genomic DNA methylation decreases in response to moderate folate depletion in elderly women. 50 Interestingly, genetic variations in genes involved in the folatemethionine pathways can further influence occurrence of these alterations. The number of hypermethylated CpG islands in tumor tissue from cancer patients correlates with inheritance of the MTR 2756A allele, suggesting that the germ-line differences in this gene may determine predisposition to cancers characterized by large numbers of DNA methylation sites.…”

Section: Discussionmentioning

confidence: 99%

Implication of the folate-methionine metabolism pathways in susceptibility to follicular lymphomas

Niclot

Pruvot

Besson

et al. 2006

Blood

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“…83 Changes in global WBC methylation from folate intake have been more frequently investigated in controlled feeding or randomized placebo-controlled intervention trials with seven studies reported, primarily using the [ 3 H]-methyl acceptor assay. 54,[84][85][86][87][88][89] The controlled feeding studies start with a folate depletion diet of around 120 μg/day for, most frequently, 7 weeks. This is then followed by high doses ranging up to 800 μg/day.…”

Section: Studies Examining Changes In Wbc Dna Methylation After Risk mentioning

confidence: 99%

DNA methylation in white blood cells

et al. 2011

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Genomic DNA methylation decreases in response to moderate folate depletion in elderly women

Abstract: DNA methylation status may be used as a functional indicator of moderately depleted folate status. The slow response to the repletion diets observed suggests that normalization of DNA methylation after moderate folate depletion may be delayed in older women.

Cited by 338 publications

References 20 publications

Increase in Plasma Homocysteine Associated with Parallel Increases in Plasma S-Adenosylhomocysteine and Lymphocyte DNA Hypomethylation

Increase in Plasma Homocysteine Associated with Parallel Increases in Plasma S-Adenosylhomocysteine and Lymphocyte DNA Hypomethylation

Implication of the folate-methionine metabolism pathways in susceptibility to follicular lymphomas

DNA methylation in white blood cells

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