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Folate supplementation increases genomic DNA methylation in the liver of elder rats

Published online by Cambridge University Press:  08 March 2007

Sang-Woon Choi ,
Simonetta Friso ,
Mary K. Keyes  and
Joel B. Mason
Sang-Woon Choi*
Affiliation:
Vitamins and Carcinogenesis Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Washington Street, Boston, MA 02111, USA
Simonetta Friso
Affiliation:
Department of Clinical and Experimental Medicine, Policlinico G. B. Rossi, University of Verona, 37134, Verona, Italy
Mary K. Keyes
Affiliation:
Vitamins and Carcinogenesis Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Washington Street, Boston, MA 02111, USA
Joel B. Mason
Affiliation:
Vitamins and Carcinogenesis Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Washington Street, Boston, MA 02111, USA Divisions of Clinical Nutrition and Gastroenterology, Tufts University School of Medicine, Boston, MA 02111, USA
*
*Corresponding author: Dr S.-W. Choi, fax +1 617 556 3309, email sang.choi@tufts.edu
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Abstract

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The availability of folate is implicated as a determinant of DNA methylation, a functionally important feature of DNA. Nevertheless, when this phenomenon has been examined in the rodent model, the effect has not always been observed. Several reasons have been postulated for the inconsistency between studies: the rodent is less dependent on folate as a methyl source than man; juvenile animals, which most studies use, are more resistant to folate depletion than old animals; methods to measure genomic DNA methylation might not be sensitive enough to detect differences. We therefore examined the relationship between folate and genomic DNA methylation in an elder rat model with a newly developed method that can measure genomic DNA methylation sensitively and precisely. Thirty-nine 1-year-old rats were divided into three groups and fed a diet containing 0, 4·5 or 18 μmol folate/kg (folate-deplete, -replete and -supplemented groups, respectively). Rats were killed at 8 and 20 weeks. At both time points, mean liver folate concentrations increased incrementally between the folate-deplete, -replete and -supplemented rats (P for trend <0·001) and by 20 weeks hepatic DNA methylation also increased incrementally between the folate-deplete, -replete and -supplemented rats (P for trend=0·025). At both time points folate-supplemented rats had significantly increased levels of DNA methylation compared with folate-deplete\ rats (P<0·05). There was a strong correlation between hepatic folate concentration and genomic DNA methylation in the liver (r 0·48, P=0·004). In the liver of this animal model, dietary folate over a wide range of intakes modulates genomic DNA methylation.

Keywords

FolateDNA methylationAgeingLiverRat
Type
Research Article
Information
British Journal of Nutrition , Volume 93 , Issue 1 , January 2005 , pp. 31 - 35
Copyright
Copyright © The Nutrition Society 2005

References

Antequera, F, Macleod, D & Bird, AP (1989) Specific protection of methylated CpGs in mammalian nuclei. Cell 58, 509–517.CrossRefGoogle ScholarPubMed
Balaghi, M, Horne, DW & Wagner, C (1993) Hepatic one-carbon metabolism in early folate deficiency in rats. Biochem J 291, 145–149.CrossRefGoogle ScholarPubMed
Bills, ND, Jones, AD & Clifford, AJ (1991) Biological activity of racemic folate mixtures fed to folate-depleted rats. J Nutr 121, 1643–1648.Google Scholar
Caudill, MA, Wang, JC, Melnyk, S, Pogribny, IP, Jernigan, S, Collins, MD, Santos-Guzman, J, Swendseid, ME, Cogger, EA & James, SJ (2001) Intracellular S -adenosylhomocysteine concentrations predict global DNA hypomethylation in tissues of methyl-deficient cystathionine beta-synthase heterozygous mice. J Nutr 131, 2811–2818.CrossRefGoogle ScholarPubMed
Choi, SW, Kim, YI, Weitzel, JN & Mason, JB (1998) Folate depletion impairs DNA excision repair in the colon of the rat. Gut 43, 93–99.CrossRefGoogle ScholarPubMed
Choi, SW, Friso, S, Dolnikowski, GG, Bagley, PJ, Edmondson, AN, Smith, DE & Mason, JB (2003) Biochemical and molecular aberrations in the rat colon due to folate depletion are age-specific. J Nutr 133, 1206–1212.CrossRefGoogle ScholarPubMed
Choumenkovitch, SF, Selhub, J, Bagley, PJ, Maeda, N, Nadeau, MR, Smith, DE & Choi, SW (2002) In the cystathionine beta-synthase knockout mouse, elevations in total plasma homocysteine increase tissue S -adenosylhomocysteine, but responses of S -adenosylmethionine and DNA methylation are tissue specific. J Nutr 132, 2157–2160.CrossRefGoogle ScholarPubMed
Crain, PF (1990) Preparation and enzymatic hydrolysis of DNA and RNA for mass spectrometry. Methods Enzymol 193, 782–790.CrossRefGoogle ScholarPubMed
De Cabo, SF, Santos, J, Fernandez-Piqueras, J (1995) Molecular and cytological evidence of S -adenosyl- l -homocysteine as an innocuous undermethylating agent in vivo. Cytogenet Cell Genet 71, 187–192.CrossRefGoogle ScholarPubMed
Drinkwater, RD, Blake, TJ, Morley, AA & Turner, DR (1989) Human lymphocytes aged in vivo have reduced levels of methylation in transcriptionally active and inactive DNA. Mutat Res 219, 29–37.Google Scholar
Fell, D, Benjamin, LE & Steele, RD (1985) Determination of adenosine and S -adenosyl derivatives of sulfur amino acids in rat liver by high performance liquid chromatography. J Chromatogr 345, 150–156.CrossRefGoogle ScholarPubMed
Friso, S & Choi, SW (2002) Gene–nutrient interactions and DNA methylation. J Nutr 132, Suppl. 8, 2382S–2387S.Google Scholar
Friso, S, Choi, SW & Girelli, D (2002a) A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci USA 99, 5606–5611.CrossRefGoogle Scholar
Friso, S, Choi, SW, Dolnikowski, GG & Selhub, J (2002b) A new method to assess genomic DNA methylation using high performance liquid chromatography–electrospray ionization mass spectrometry. Anal Chem 74, 4526–4531.CrossRefGoogle Scholar
Goodman, JI & Counts, JL (1993) Hypomethylation of DNA: a possible nongenotoxic mechanism underlying the role of cell proliferation in carcinogenesis. Environ Health Perspect 101, Suppl. 5, 169–172.Google Scholar
Hoal-van, Helden, EG, van & Helden, PD (1989) Age-related methylation changes in DNA may reflect the proliferative potential of organs. Mutat Res 219, 263–266.Google Scholar
Holliday, R (1986) Strong effects of 5-azacytidine on the in vitro lifespan of human diploid fibroblasts. Exp Cell Res 166, 543–552.Google Scholar
Holliday, R (1987) The inheritance of epigenetic defects. Science 238, 163–170.CrossRefGoogle ScholarPubMed
Jacob, RA, Gretz, DM, Taylor, PC, James, SJ, Pogribny, IP, Miller, BJ, Henning, SM & Swendseid, ME (1998) Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. J Nutr 128, 1204–1212.Google Scholar
Kim, YI, Christmas, JK, Fleet, JC, Cravo, ML, Salomon, RN, Smith, D, Ordovas, J, Selhub, J & Mason, JB (1995) Moderate folate deficiency does not cause global hypomethylation of hepatic and colonic DNA or c-myc-specific hypomethylation of colonic DNA in rats. Am J Clin Nutr 61, 1083–1090.CrossRefGoogle ScholarPubMed
Kim, YI, Salomon, RN, Graeme-Cook, F, Choi, SW, Smith, DE, Dallal, GE & Mason, JB (1996) Dietary folate protects against the development of macroscopic colonic neoplasms in a dose-responsive manner in rats. Gut 39, 732–740.Google Scholar
Kim, YI, Pogribny, IP, Basnakian, AG, Miller, JW, Selhub, J, James, SJ & Mason, JB (1997) Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene. Am J Clin Nutr 65, 46–52.CrossRefGoogle ScholarPubMed
MacKenzie, RE (1984) Biogenesis and interconversion of substituted tetrahydrofolates Folate and Pterins, 255–306 [Blakley, RL, Benkovic, SJ, editors]. New York: Wiley.Google Scholar
Mays-Hoopes, L, Chao, W, Butcher, HC & Huang, RC (1986) Decreased methylation of the major mouse long interspersed repeated DNA during aging and in myeloma cells. Dev Genet 7, 65–73.CrossRefGoogle ScholarPubMed
Rampersaud, GC, Kauwell, GP, Hutson, AD, Cerda, JJ & Bailey, LB (2000) Genomic DNA methylation decreases in response to moderate folate depletion in elderly women. Am J Clin Nutr 72, 998–1003.CrossRefGoogle ScholarPubMed
Razin, A & Cedar, H (1991) DNA methylation and gene expression. Microbiol Rev 55, 451–458.CrossRefGoogle ScholarPubMed
Reeves, PG, Nielsen, FH, Fahey, GC Jr (1993) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 123, 1939–1951.Google Scholar
Ronucci, L, Ponz, de, Leon, M, Scalmati, A, Malagoli, G, Pratissoli, S, Perini, M & Chahin, NJ (1988) The influence of age on colonic epithelial cell proliferation. Cancer 62, 2373–2377.3.0.CO;2-Y>CrossRefGoogle Scholar
Sohn, KJ, Stempak, JM, Reid, S, Shirwadkar, S, Mason, JB & Kim, YI (2003) The effect of dietary folate on genomic and p53-specific DNA methylation in rat colon. Carcinogenesis 24, 81–90.CrossRefGoogle ScholarPubMed
Tamura, T (1990) Microbiological assay of folate Folic Acid Metabolism in Health and Disease 1st ed. vol. 13, pp. 121–137 [Picciano, MF, Stokstad, ELR, Gregory, JF III, editors]. New York: Wiley-Liss.Google Scholar
Varela-Moreiras, G & Selhub, J (1992) Long-term folate deficiency alters folate content and distribution differentially in rat tissues. J Nutr 122, 986–991.CrossRefGoogle ScholarPubMed
Walzem, RL & Clifford, AJ (1988) Folate deficiency in rats fed diets containing free amino acids or intact proteins. J Nutr 118, 1089–1096.Google Scholar
Wilson, VL & Jones, PA (1983) DNA methylation decreases in aging but not in immortal cells. Science 20, 1055–1057.Google Scholar
Wilson, VL, Smith, RA, Ma, S & Cutler, RG (1987) Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem 262, 9948–9951.CrossRefGoogle ScholarPubMed
Yi, P, Melnyk, S, Pogribna, M, Pogribny, IP, Hine, RJ & James, SJ (2000) Increase in plasma homocysteine associated with parallel increases in plasma S -adenosylhomocysteine and lymphocyte DNA hypomethylation. J Biol Chem 275, 29318–29323.Google Scholar