![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
*
Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892 and
National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079
2To whom correspondence should be addressed. E-mail: sr75k{at}nih.gov.
KEY WORDS: • DNA methylation • S-adenosylmethionine • diet • cancer • disease
 |
Foreword |
|---|
 TOP Foreword Introductory commentsProceedings overviewLITERATURE CITED |
|---|
,2
). The evidence that DNA methylation is influenced by diet and dietary factors arises from both preclinical and clinical studies. For example, liver DNA is hypomethylated in rats continuously fed methyl-deficient diets (3
). Hypomethylation of specific cytosine guanine dinucleotide (CpG) sites within several genes, for example, c-myc (myelocytomatosis oncogene), c-fos (FBJ osteosarcoma oncogene) and H-ras (Harvey rat sarcoma virus oncogene), also was observed in rat liver. Moreover, folate depletion resulted in lymphocyte DNA hypomethylation in postmenopausal women, which was reversed following folate repletion (4
). To summarize recent findings and identify research limitations in this exciting area, the National Cancer Institute and the Food and Drug Administration, in collaboration with other Institutes of the National Institutes of Health, the American Society for Nutritional Sciences and the International Life Sciences Institute, North America, convened a workshop from August 6 through August 8, 2001, at the Natcher Conference Center on the National Institutes of Health campus in Bethesda, MD, entitled "Trans-HHS Workshop: Diet, DNA Methylation Processes and Health." The manuscripts included in this supplement to The Journal of Nutrition provide a broad synopsis of the presentations made at this Workshop. This Workshop was designed to enhance knowledge and understanding about the role of dietary factors and genetic polymorphisms in methyl metabolism and DNA methylation processes and to increase the appreciation of how shifts in these processes influence growth, development and disease prevention. The Workshop showcased a range of diseases in which abnormal methylation and diet appear to be involved. The meeting was organized into several sessions beginning with an overview of DNA methylation and 1-carbon metabolism, leading to discussions about associations between dietary methyl intake and/or genetic polymorphisms and disease risk. The program continued with presentations on the biochemistry of methylation, on its role in cell and molecular biology and on mechanistic studies on DNA methylation and disease and ended with issues that have relevance in public health such as folate fortification and folate intake. Session topics included overview topics, dietary methyl donor insufficiency and human disease risk, methyl metabolism and biochemistry, mechanisms and consequences of aberrant DNA methylation in physiological processes, research applications in DNA methylation, cell and molecular biology of DNA methylation and public health issues.
The meeting brought together basic science investigators, clinical investigators, epidemiologists and other health professionals from various disciplines with the goal of encouraging collaboration and promoting active discussion and exchange of ideas for further research concerning diet, DNA methylation processes and health. Additional outcomes of the Workshop include the proceedings in this Journal supplement and an executive summary, which is available online at http://www3.cancer.gov/prevention/nutrition/methylation.html.Most importantly, recommendations for future research were articulated throughout the meeting. It is our hope that various individuals and groups will utilize these suggestions to advance this area of investigation (See the Appendix of this Journal supplement). The Nutritional Science Research Group of the Division of Cancer Prevention at the National Cancer Institute is formulating strategies to promote research that will advance the understanding about diet, DNA methylation and cancer prevention interactions.
|
Introductory comments |
|---|
|
TOPForewordIntroductory commentsProceedings overviewLITERATURE CITED |
|---|
60–90% of all CpG sequences in the genome are methylated, whereas unmethylated CpG dinucleotides are mainly clustered in CpG-rich sequences, termed "CpG islands," within the promoter regions of genes (5
). Normally, both core promoter and transcription start site are included within the CpG island, and if the corresponding gene transcription factors are available and the CpG island remains in an unmethylated state with an open chromatin configuration associated with hyperacetylated histones, the transcription of that particular gene will occur (6
). Methylation of CpG islands, however, inhibits gene transcription by directly impeding the binding of transcription factors to their cis-acting sites and/or by promoting the binding of methyl-DNA-binding proteins, which restrict access of transcription factors to DNA (7
). Thus, DNA methylation appears to be an important epigenetic mechanism of transcriptional control.
Genomic methylation patterns are frequently altered in tumor cells, with global hypomethylation accompanying region-specific hypermethylation events. DNA hypomethylation has been shown to lead to chromosomal instability in embryonic stem cells that are null for the DNA methyltransferase 1 gene and in cells treated with the demethylating agent 5-azadeoxycytidine (8
). Genomic instability can cause mutations in genes, thereby representing an indirect way in which changes in methylation patterns can affect gene expression. Hypomethylation within a number of genes has been found in primary cancers, including known oncogenes such as c-myc and H-ras (1
). It has been proposed that such hypomethylation may lead to inappropriate activation of these genes. Perhaps more widely studied at present is the observation that CpG islands in promoter regions of a number of genes, either known to be involved in carcinogenesis (e.g., tumor suppressor genes and genes involved in DNA repair, growth regulation and apoptosis) or candidate tumor suppressor genes, have been found to be hypermethylated in many types of human cancer (7
).
Dietary factors that are involved in 1-carbon metabolism (Fig. 1
) that are likely to have an impact on DNA methylation processes include folate, vitamin B-12 (cobalamin), vitamin B-6 (pyridoxine (PN), vitamin B-2 (riboflavin), methionine, choline and alcohol (9
). Normally in 1-carbon metabolism, a carbon unit from serine or glycine is transferred to tetrahydrofolate (THF) to form 5,10-methylenetetrahydrofolate. This compound is either used for the synthesis of thymidine, which is incorporated into DNA, oxidized to formyl-THF for the synthesis of purines, which are building blocks of RNA and DNA, or reduced to 5-methyltetrahydrofolate and used to methylate homocysteine to form methionine, a reaction catalyzed by a vitamin B-12-containing methyltransferase. Methionine is converted to S-adenosylmethionine, a universal donor of methyl groups, which methylates DNA, RNA, hormones, neurotransmitters, membrane lipids, proteins and other molecules (9
).
|
–14
). At present the epidemiological evidence linking the 1-carbon nutrients with cancer is strongest for the relationship between folate and colorectal cancer (15
). The effect of folate on colorectal cancer may be modulated by alcohol, methionine, vitamin B-12, riboflavin and polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20) (16
). MTHFR catalyzes reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Two polymorphisms that reduce MTHFR activity have been described: cytosine-to-thymine transition at position 677 (C677T) and cytosine-to-adenine transition at position 1298. Homozygosity for the C677T mutation or combined heterozygosity for both polymorphisms each results in an increased requirement for folic acid to maintain usual blood folate concentrations and usual homocysteine remethylation (17
). Evidence suggests that the C677T MTHFR variant may increase colorectal cancer risk only when folate is deficient, but the role of MTHFR in modulating the risk of colorectal and other cancers needs to be clarified (16
). Diminished activity of MTHFR also has been associated with increased risk of developing atherosclerosis (18
), neurological disorders (19
) and birth defects (17
).
Studies in animals have shown that methyl/folate deprivation causes cancer of the liver (20
). Methyl-deficient diets also have resulted in global DNA hypomethylation (21
) as well as oncogene hypomethylation (22
,23
). In one study with a methyl-deficient diet, hypomethylation of c-myc, c-fos and H-ras was associated with elevated levels of mRNA for these same genes (3
). DNA methylation patterns of the p53 (Li-Fraumeni syndrome) gene also have been evaluated during multistage hepatocarcinogenesis in rats chronically fed a methyl-deficient diet (24
). In the resultant preneoplastic hepatic nodules, the level of p53 mRNA was increased and associated with hypomethylation in the coding region of the gene. In tumor tissue, however, p53 mRNA was decreased and associated with relative hypermethylation. It is thus envisioned that one mechanism through which dietary factors influence gene expression is alteration of gene-specific DNA methylation patterns. These observations have importance in understanding cancer and other pathologies including birth defects and atherosclerosis.
|
Proceedings overview |
|---|
|
TOPForewordIntroductory commentsProceedings overviewLITERATURE CITED |
|---|
The manuscripts in this proceedings are intended to summarize the current state of knowledge, to identify gaps in this knowledge and to set the stage for future research. The study of the relationship between diet and DNA methylation processes is truly in its infancy but is deserving of more attention. We hope that these proceedings will serve as a stimulus for research to advance the field of diet, nutrition and disease prevention. Moreover, it is our hope that new knowledge will evolve in this field and be applied toward the promotion of health and disease prevention.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
3 Abbreviations used: C677T, cytosine-to-thymine transition at position 677; c-fos, FBJ osteosarcoma oncogene; c-myc, myelocytomatosis oncogene; CpG, cytosine guanine dinucleotide; H-ras, Harvey rat sarcoma virus oncogene; MTHFR, methylenetetrahydrofolate reductase; PN, pyridoxine; THF, tetrahydrofolate.
|
LITERATURE CITED |
|---|
|
TOPForewordIntroductory commentsProceedings overviewLITERATURE CITED |
|---|
1. Costello, J. F. & Plass, C. (2001) Methylation matters. J. Med. Genet. 38:285-303.
2. Poirier, L. A., Brown, A. T., Fink, L. M., Wise, C. K., Randolph, C. J., Delongchamp, R. R. & Fonseca, V. A. (2001) Blood S-adenosylmethionine concentrations and lymphocyte methylenetetrahydrofolate reductase activity in diabetes mellitus and diabetic nephropathy. Metabolism 50:1014-1018.[Medline]
3. Christman, J. K., Sheikhnejad, G., Dizik, M., Abileah, S. & Wainfan, E. (1993) Reversibility of changes in nucleic acid methylation and gene expression induced in rat liver by severe dietary methyl deficiency. Carcinogenesis 14:551-557.
4. Jacob, R. A., Gretz, D. M., Taylor, P. C., James, S. J., Pogribny, I. P., Miller, B. J., Henning, S. M. & Swendseid, M. E. (1998) Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. J. Nutr. 128:1204-1212.
5. Ng, H. H. & Bird, A. (1999) DNA methylation and chromatin modification. Curr. Opin. Genet. Dev. 9:158-163.[Medline]
6. Esteller, M. & Herman, J. G. (2002) Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumors. J. Pathol. 196:1-7.[Medline]
7. Baylin, S. B., Herman, J. G., Graff, J. R., Vertino, P. M. & Issa, J.-P. (1998) Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv. Cancer Res. 72:141-196.[Medline]
8. Chen, R. Z., Pettersson, U., Beard, C., Jackson-Gruby, L. & Jaenisch, R. (1998) DNA hypomethylation leads to elevated mutation rates. Nature 395:89-93.[Medline]
9. Selhub, J. (2002) Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J. Nutr. Health Aging 6:39-42.[Medline]
10. Stolzenberg-Solomon, R. Z., Albanes, D., Nieto, F. J., Hartman, T. J., Tangrea, J. A., Rautalahti, M., Sehlub, J., Virtamo, J. & Taylor, P. R. (1999) Pancreatic cancer risk and nutrition-related methyl-group availability indicators in male smokers. J. Natl. Cancer Inst. 91:535-441.
11. Hsing, A. W., Hansson, L. E., McLaughlin, J. K., Nyren, O., Blot, W. J., Ekbom, A. & Fraumeni, J. F., Jr. (1993) Pernicious anemia and subsequent cancer: a population-based cohort study. Cancer 71:745-750.[Medline]
12. Giovannucci, E., Rimm, E. B., Ascherio, A., Stampfer, M. J., Colditz, G. A. & Willett, W. C. (1995) Alcohol, low-methionine-low-folate diets, and risk of colon cancer in men. J. Natl. Cancer Inst. 87:265-273.
13. Shrubsole, M. J., Jin, F., Dai, Q., Shu, X. O., Potter, J. D., Hebert, J. R., Gao, Y. T. & Zheng, W. (2001) Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Res. 61:7136-7141.
14. Butterworth, C. E., Jr., Hatch, K. D., Macaluso, M., Cole, P., Sauberlich, H. E., Soong, S. J., Borst, M. & Baker, V. V. (1992) Folate deficiency and cervical dysplasia. J. Am. Med. Assoc. 267:528-533.
15. Eichholzer, M., Luthy, J., Moser, U. & Fowler, B. (2001) Folate and the risk of colorectal, breast and cervix cancer: the epidemiological evidence. Swiss Med. Wkly. 131:539-549.[Medline]
16. Ryan, B. M. & Weir, D. G. (2001) Relevance of folate metabolism in the pathogenesis of colorectal cancer. J. Lab. Clin. Med. 138:164-176.[Medline]
17. Van der Put, N. M., Gabreëls, F., Stevens, E. M., Smeitink, J. A., Trijbels, F. J., Eskes, T. K., van den Heuvel, L. P. & Blom, H. J. (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?. Am. J. Hum. Genet 62:1044-1051.[Medline]
18. Blom, H. J. (1998) Mutated 5,10-methylenetetrahydrofolate reductase and moderate hyperhomocysteinaemia. Eur. J. Pediatr. 157:131s-134s.
19. Walk, D., Kang, S. S. & Horwitz, A. (1994) Intermittent encephalopathy, reversible nerve conduction slowing, and MRI evidence of cerebral white matter disease in methylenetetrahydrofolate reductase deficiency. Neurology 44:344-347.
20. Mikol, Y. B., Hoover, K. L., Creasia, D. & Poirier, L. A. (1983) Hepatocarcinogenesis in rats fed methyl-deficient, amino acid-defined diets. Carcinogenesis 4:1619-1629.
21. Poirier, L. A. (1986) The role of methionine in carcinogenesis in vivo. Adv. Exp. Med. Biol. 206:269-282.[Medline]
22. Bhave, M. R., Wilson, M. J. & Poirier, L. A. (1988) c-H-ras and c-K-ras gene hypomethylation in the livers and hepatomas of rats fed methyl-deficient, amino acid-defined diets. Carcinogenesis 9:343-348.
23. Zapisek, W. F., Cronin, G. M., Lyn-Cook, B. D. & Poirier, L. A. (1992) The onset of oncogene hypomethylation in the livers of rats fed methyl-deficient, amino acid-defined diets. Carcinogenesis 13:1869-1872.
24. Pogribny, I. P., Miller, B. J. & James, S. J. (1997) Alterations in hepatic p53 gene methylation patterns during tumor progression with folate/methyl deficiency in the rat. Cancer Lett. 115:31-38.[Medline]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
