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Nutrition and Disease

A Folate- and Methyl-Deficient Diet Alters the Expression of DNA Methyltransferases and Methyl CpG Binding Proteins Involved in Epigenetic Gene Silencing in Livers of F344 Rats^1,2

Kalpana Ghoshal^*,3, Xin Li^*, Jharna Datta^*, Shoumei Bai^*, Igor Pogribny, Marta Pogribny, Yan Huang^*, Donn Young^** and Samson T. Jacob^*,**,,3

^* Department of Molecular and Cellular Biochemistry, ^** Comprehensive Cancer Center, and Department of Internal Medicine, Ohio State University, Columbus, OH 43210 and Division of Biochemical Toxicology, Food and Drug Administration, National Center for Toxicological Research, Jefferson, AR 72079

³ To whom correspondence should be addressed. E-mail: jacob.42{at}osu.edu or ghoshal.1{at}osu.edu.

Aberrations in methylation profile of the genome occur in human cancers induced by folate deficiency. To elucidate the underlying mechanism, male F344 rats were fed a diet deficient in L-methionine and devoid of folic acid and choline (FMD diet), which is known to induce hepatocellular carcinomas. We investigated changes in the DNA methylation machinery, namely, de novo DNA methyltransferases (Dnmt3a and 3b), maintenance DNA methyltransferase (Dnmt1), and methyl CpG binding proteins (MBDs), in rat livers during early stages of tumorigenesis. RT-PCR and Western blot analyses revealed differential expression of these proteins in the livers of rats fed the FMD diet. Although the hepatic Dnmt1 mRNA level declined with age (P < 0.001), it was elevated (P < 0.001) in deficient rats compared with controls. The changes in hepatic Dnmt1 protein level with the diet correlated with its mRNA levels (r = 0.60, P = 0.002). Similarly, the Dnmt3a mRNA level was elevated in rats fed the FMD diet (P < 0.001), whereas the Dnmt3b level (mRNA and protein) was not affected by diet or age. Compared with controls, hepatic MBD1–3 RNA levels increased (P < 0.001) and the protein levels of MBD1, 2, and 4 were elevated (P < 0.001) in the deficient rats. In both diet groups, hepatic MBD2 protein decreased (P < 0.001), whereas MeCP2 protein increased (P < 0.001) with age. These results demonstrate that a combined folate and methyl deficiency alters components of the DNA methylation machinery by both transcriptional and posttranscriptional mechanisms during early stages of hepatocarcinogenesis.

KEY WORDS: • hepatocarcinogenesis • folate- and methyl-deficient diet • Dnmt1/3a/3b • MBD1–4

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