Hypomethylation of hepatic nuclear DNA in rats fed with a carcinogenic methyl-deficient diet

Wilson, Marvin C.; Shivapurkar, Narayan; Poirier, Lionel A.

doi:10.1042/bj2180987

Cited by 153 publications

(75 citation statements)

References 22 publications

(25 reference statements)

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“…For example, rats fed a diet deficient in methionine and choline exhibited a change from normal DNA methylation to global DNA hypomethylation that included specific gene hypomethylation (94,95). A folate-deficient diet introduced to healthy rats led to DNA hypomethylation in the brain (96).…”

Section: Dietary Folate and Dna Methylationmentioning

confidence: 99%

Could Epigenetics Play a Role in the Developmental Origins of Health and Disease?

et al. 2007

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Section: Dietary Folate and Dna Methylationmentioning

confidence: 99%

Could Epigenetics Play a Role in the Developmental Origins of Health and Disease?

et al. 2007

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“…Animals fed diets deficient in methyl donors (choline and methionine) have hypomethylated DNA [49][50][51]. These deficiencies have been shown to cause both global [52] and gene-specific hypomethylation [53]. However, research has focused on the carcinogenic effects of methyl-deficient diets; e.g.…”

Section: Animal Studiesmentioning

confidence: 99%

Phosphatidylcholine functional foods and nutraceuticals: A potential approach to prevent non‐alcoholic fatty liver disease

Duric

Sivanesan

Bakovic

2012

Euro J Lipid Sci & Tech

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Non‐alcoholic fatty liver disease (NAFLD) is the most common liver condition in the developed world and may progress to more severe forms of disease such as cirrhosis or liver cancer. Thus, steps taken to reduce its prevalence through preventative nutritional approaches such as functional foods and nutraceuticals (FFN) should be pursued. It is well known that certain lipotropic nutrients such as choline and metabolites betaine and phosphatidylcholine (PC; lecithin) could prevent or alleviate fatty liver through a variety of mechanisms, including increased hepatic VLDL secretion. Animal and human studies have demonstrated clear protective effects of choline, betaine and PC for NAFLD as well as possible roles in CVD prevention from epidemiological data. Currently, choline consumption is below dietary recommendations due in large part to a general lack of understanding regarding the importance of this nutrient for human health. As lecithin is commonly added (in small amounts) in many processed foods due to its functional capabilities, it is projected that increasing its abundance in the food supply and increasing consumer education and acceptance of lecithin‐based functional foods and nutraceuticals may represent a progressive step towards preventing liver and whole‐body metabolic pathologies in many areas of the world.

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“…DNA methylation is a major epigenetic mechanism that mediates genomic imprinting and X-chromosome inactivation and regulates tissue-specific gene expression, cell differentiation, and chromatin structure (20,21). The reported effects of choline or methyl group deficiency on global DNA methylation vary; most authors observed hypomethylation (22)(23)(24)(25)(26)(27)(28)(29), some no change (30), and some hypermethylation (31,32), suggesting that DNA methylation may respond to the supply of methyl groups in a complex fashion that includes alterations in the activities of DNA methylating and/or demethylating enzymes. DNA methylation patterns acquired during development may be inherited through the cell divisions in a process catalyzed by DNA methyltransferase 1 (DNMT1) that methylates hemimethylated CpG sites and, thus, restores the parental methylation pattern on the daughter DNA strand after DNA replication (33).…”

mentioning

confidence: 99%

Gestational Choline Deficiency Causes Global and Igf2 Gene DNA Hypermethylation by Up-regulation of Dnmt1 Expression

Kovacheva

Mellott

Davison

et al. 2007

Journal of Biological Chemistry

208

191

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During gestation there is a high demand for the essential nutrient choline. Adult rats supplemented with choline during embryonic days (E) 11-17 have improved memory performance and do not exhibit age-related memory decline, whereas prenatally choline-deficient animals have memory deficits. Choline, via betaine, provides methyl groups for the production of S-adenosylmethionine, a substrate of DNA methyltransferases (DNMTs). We describe an apparently adaptive epigenomic response to varied gestational choline supply in rat fetal liver and brain. S-Adenosylmethionine levels increased in both organs of E17 fetuses whose mothers consumed a choline-supplemented diet. Surprisingly, global DNA methylation increased in choline-deficient animals, and this was accompanied by overexpression of Dnmt1 mRNA. Previous studies showed that the prenatal choline supply affects the expression of multiple genes, including insulin-like growth factor 2 (Igf2), whose expression is regulated in a DNA methylation-dependent manner. The differentially methylated region 2 of Igf2 was hypermethylated in the liver of E17 choline-deficient fetuses, and this as well as Igf2 mRNA levels correlated with the expression of Dnmt1 and with hypomethylation of a regulatory CpG within the Dnmt1 locus. Moreover, mRNA expression of brain and liver Dnmt3a and methyl CpG-binding domain 2 (Mbd2) protein as well as cerebral Dnmt3l was inversely correlated to the intake of choline. Thus, choline deficiency modulates fetal DNA methylation machinery in a complex fashion that includes hypomethylation of the regulatory CpGs within the Dnmt1 gene, leading to its overexpression and the resultant increased global and gene-specific (e.g. Igf2) DNA methylation. These epigenomic responses to gestational choline supply may initiate the long term developmental changes observed in rats exposed to varied choline intake in utero.An adequate supply of essential nutrients involved in the metabolism of methyl groups, including folic acid, vitamin B 12 , and choline, is central for normal development of the fetus. This is perhaps best exemplified by the discovery that the dietary supply of folic acid, a vitamin that acts as a coenzyme in one-carbon transfer pathways, during the periconceptual period is critical in prevention of neural tube defects (1). Studies in animal models (2-5) as well as recent epidemiological investigations in humans (6) indicate that choline intake during gestation is particularly important for the normal development and function of the central nervous system. In a frequently used experimental model that employs offspring of pregnant rats or mice consuming diets of varying choline content during the 7-day period of the second half of gestation (embryonic days E11-17), prenatal choline deficiency causes deficits in certain memory tasks (7), whereas prenatal choline supplementation leads to enhanced memory and attention and prevents agerelated memory decline (7-13). These behavioral changes are accompanied by electrophysiological, neuroanatomical, and neuro...

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Hypomethylation of hepatic nuclear DNA in rats fed with a carcinogenic methyl-deficient diet

Cited by 153 publications

References 22 publications

Could Epigenetics Play a Role in the Developmental Origins of Health and Disease?

Could Epigenetics Play a Role in the Developmental Origins of Health and Disease?

Phosphatidylcholine functional foods and nutraceuticals: A potential approach to prevent non‐alcoholic fatty liver disease

Gestational Choline Deficiency Causes Global and Igf2 Gene DNA Hypermethylation by Up-regulation of Dnmt1 Expression

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