QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Online Supporting Material Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ghoshal, K. Articles by Jacob, S. T. Search for Related Content PubMed PubMed Citation Articles by Ghoshal, K. Articles by Jacob, S. T. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB (L)-METHIONINE Medline Plus Health Information Folic Acid

---

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

This article has been cited by other articles:

				D. Desaulniers, G.-h. Xiao, H. Lian, Y.-L. Feng, J. Zhu, J. Nakai, and W. J. Bowers Effects of Mixtures of Polychlorinated Biphenyls, Methylmercury, and Organochlorine Pesticides on Hepatic DNA Methylation in Prepubertal Female Sprague-Dawley Rats International Journal of Toxicology, July 1, 2009; 28(4): 294 - 307. [Abstract] [Full Text] [PDF]

				E. Hervouet, E. Debien, L. Campion, J. Charbord, J. Menanteau, F. M. Vallette, and P.-F. Cartron Folate Supplementation Limits the Aggressiveness of Glioma via the Remethylation of DNA Repeats Element and Genes Governing Apoptosis and Proliferation Clin. Cancer Res., May 15, 2009; 15(10): 3519 - 3529. [Abstract] [Full Text] [PDF]

				K. T. Williams, T. A. Garrow, and K. L. Schalinske Type I Diabetes Leads to Tissue-Specific DNA Hypomethylation in Male Rats J. Nutr., November 1, 2008; 138(11): 2064 - 2069. [Abstract] [Full Text] [PDF]

				J. Datta, H. Kutay, M. W. Nasser, G. J. Nuovo, B. Wang, S. Majumder, C.-G. Liu, S. Volinia, C. M. Croce, T. D. Schmittgen, et al. Methylation Mediated Silencing of MicroRNA-1 Gene and Its Role in Hepatocellular Carcinogenesis Cancer Res., July 1, 2008; 68(13): 5049 - 5058. [Abstract] [Full Text] [PDF]

				J. Kotsopoulos, K.-J. Sohn, and Y.-I. Kim Postweaning Dietary Folate Deficiency Provided through Childhood to Puberty Permanently Increases Genomic DNA Methylation in Adult Rat Liver J. Nutr., April 1, 2008; 138(4): 703 - 709. [Abstract] [Full Text] [PDF]

				B. Sadikovic, J. Andrews, D. Carter, J. Robinson, and D. I. Rodenhiser Genome-wide H3K9 Histone Acetylation Profiles Are Altered in Benzopyrene-treated MCF7 Breast Cancer Cells J. Biol. Chem., February 15, 2008; 283(7): 4051 - 4060. [Abstract] [Full Text] [PDF]

				A. Y. Jung, E. M. Poole, J. Bigler, J. Whitton, J. D. Potter, and C. M. Ulrich DNA Methyltransferase and Alcohol Dehydrogenase: Gene-Nutrient Interactions in Relation to Risk of Colorectal Polyps Cancer Epidemiol. Biomarkers Prev., February 1, 2008; 17(2): 330 - 338. [Abstract] [Full Text] [PDF]

				M. E. Vahter Interactions between Arsenic-Induced Toxicity and Nutrition in Early Life J. Nutr., December 1, 2007; 137(12): 2798 - 2804. [Abstract] [Full Text] [PDF]

				V. P. Kovacheva, T. J. Mellott, J. M. Davison, N. Wagner, I. Lopez-Coviella, A. C. Schnitzler, and J. K. Blusztajn Gestational Choline Deficiency Causes Global and Igf2 Gene DNA Hypermethylation by Up-regulation of Dnmt1 Expression J. Biol. Chem., October 26, 2007; 282(43): 31777 - 31788. [Abstract] [Full Text] [PDF]

				T. M. Welzel, H. A. Katki, L. C. Sakoda, A. A. Evans, W. T. London, G. Chen, S. O'Broin, F.-M. Shen, W.-Y. Lin, and K. A. McGlynn Blood Folate Levels and Risk of Liver Damage and Hepatocellular Carcinoma in a Prospective High-Risk Cohort Cancer Epidemiol. Biomarkers Prev., June 1, 2007; 16(6): 1279 - 1282. [Abstract] [Full Text] [PDF]