Reversibility of changes in nucleic acid methylation and gene expression induced in rat liver by severe dietary methyl deficiency

Abstract

As we have reported previously, both DNA and tRNA become hypomethylated in livers of rats fed a cancer promoting, methyl-deficient diet (MDD) for as short a period as one week. Within the same period, activities of tRNA and DNA methyltransferases (MTases) increase and levels of mRNAs for several genes believed to have roles in growth regulation are altered. These diet-induced changes in nucleic acid methylation and gene expression increased in extent when MDD was fed continuously for four weeks. We also observed hypomethylation of specific CCGG sites within several genes for which mRNA levels were increased. These included c-myc, c-fos and c-Ha-ras. To investigate the reversibility of such diet-induced alterations in methylation and gene expression, animals were fed MDD for four weeks, after which a diet supplemented with adequate sources of methyl groups (CSD) was fed for 1-3 weeks. One to two weeks after the restoration of an adequate diet, the overall extent of methylation of tRNA and DNA from livers of these rats did not differ from that of tRNA and DNA from livers of age matched animals continually maintained on CSD. At the same time, activities of MTases in the liver dropped to normal values. Levels of mRNAs for all genes studied returned to control levels within three weeks after ending MDD feeding, although at different rates. In contrast, MDD-induced hypomethylation of some HpaII sites in c-myc, c-fos and c-Ha-ras genes persisted after 3 weeks refeeding of an adequate diet. These results, which demonstrate that most of the effects of MDD on the parameters we have studied occur rapidly and are essentially reversible, are consistent with the role of MDDs as promoters of hepatocarcinogenesis. However, the finding that unmethylated sites persist in genes that play a role in growth regulation suggests a mechanism by which intermittent or long term exposure to MDDs could result in heritable phenotypic changes in some hepatocytes that lead to hyperplasia and tumorigenesis.

Folate, vitamin B6, vitamin B12 and methionine intakes and risk for nasopharyngeal carcinoma in Chinese adults: a matched case–control study

“…Vitamin B 6 and B 12 play an important role as co-enzymes in onecarbon metabolism (8) . Vitamin B 6 mediates the conversion of uracil to thymidylate to regenerate 5,10-methylenetetrahydrofolate (8) .…”

“…Vitamin B 6 mediates the conversion of uracil to thymidylate to regenerate 5,10-methylenetetrahydrofolate (8) . In addition, vitamin B 6 may influence NPC risk through its antioxidant properties, as studies have reported that vitamin B 6 MET, metabolic equivalent.…”

“…Vitamin B 12 is needed for methionine synthase and is responsible for catalysing the methylation of homocysteine to methionine (8) . However, we failed to find any significant association for vitamin B 12 in our study, probably because of the significantly lower levels of vitamin B 12 (2·30 μg/d) compared with other nutrients (e.g.…”

Epigenetics and cancer

“…Loss of DNA methylation has also been linked to nutrition, as lack of S-adenosylmethione, the primary methyl donor in the cell, has been shown to predispose to cancer (Huang 2002). A decrease in global methylation can be detected prior to tumor formation in rats maintained on a methyldeficient diet (Christman et al 1993;Pogribny et al 1997), and hypomethylation has been found to increase the expression of several known oncogenes including CYCLIN D2 (Oshimo et al 2003), BCL2 (Hanada et al 1993, and HRAS (Feinberg and Vogelstein 1983b). On a more positive note, global demethylation results in the expression of "cancer and testis-specific" antigens (De Smet et al 1996;Banchereau et al 2003).…”

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

“…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).…”