Global DNA and p53 region-specific hypomethylation in human colonic cells is induced by folate depletion and reversed by folate supplementation

Gillian R Wasson, Angela P McGlynn, Helene McNulty, Sharleen L O'Reilly, Valerie McKelvey-Martin, George McKerr, JJ Strain, John Scott, Stephen Downes

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

There is increasing evidence to suggest that reduced folate status may be a causative factor in carcinogenesis, particularly colorectal carcinogenesis. Folate is essential for the synthesis of S-adenosylmethionine, the methyl donor required for all methylation reactions in the cell, including the methylation of DNA. Global DNA hypomethylation appears to be an early, and consistent, molecular event in carcinogenesis. We have examined the effects of folate depletion on human-derived cultured colon carcinoma cells using 2 novel modifications to the Comet (single cell gel electrophoresis) assay to detect global DNA hypomethylation and gene region-specific DNA hypomethylation. Colon cells cultured in folate-free medium for 14 d showed a significant increase in global DNA hypomethylation compared with cells grown in medium containing 3 mu mol/L folic acid. This was also true at a gene level, with folate-deprived cells showing significantly more DNA hypomethylation in the region of the p53 gene. In both cases, the effects of folate depletion were completely reversed by the reintroduction of folic acid to the cells. These results confirm that decreased folate levels are capable of inducing DNA hypomethylation in colon cells and particularly in the region of the p53 gene, suggesting that a more optimal folate status in vivo may normalize any DNA hypomethylation, offering potential protective effects against carcinogenesis. This study also introduces 2 novel functional biomarkers of DNA hypomethylation and demonstrates their suitability to detect folate depletion-induced molecular changes.
LanguageEnglish
Pages2748-2753
JournalJournal of Nutrition
Volume136
Issue number11
Publication statusPublished - Nov 2006

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Folic Acid
DNA
Carcinogenesis
Colon
p53 Genes
S-Adenosylmethionine
Comet Assay
DNA Methylation
Methylation
Genes
Cultured Cells
Biomarkers
Carcinoma

Cite this

Wasson, G. R., McGlynn, A. P., McNulty, H., O'Reilly, S. L., McKelvey-Martin, V., McKerr, G., ... Downes, S. (2006). Global DNA and p53 region-specific hypomethylation in human colonic cells is induced by folate depletion and reversed by folate supplementation. Journal of Nutrition, 136(11), 2748-2753.
Wasson, Gillian R ; McGlynn, Angela P ; McNulty, Helene ; O'Reilly, Sharleen L ; McKelvey-Martin, Valerie ; McKerr, George ; Strain, JJ ; Scott, John ; Downes, Stephen. / Global DNA and p53 region-specific hypomethylation in human colonic cells is induced by folate depletion and reversed by folate supplementation. In: Journal of Nutrition. 2006 ; Vol. 136, No. 11. pp. 2748-2753.
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Wasson, GR, McGlynn, AP, McNulty, H, O'Reilly, SL, McKelvey-Martin, V, McKerr, G, Strain, JJ, Scott, J & Downes, S 2006, 'Global DNA and p53 region-specific hypomethylation in human colonic cells is induced by folate depletion and reversed by folate supplementation', Journal of Nutrition, vol. 136, no. 11, pp. 2748-2753.

Global DNA and p53 region-specific hypomethylation in human colonic cells is induced by folate depletion and reversed by folate supplementation. / Wasson, Gillian R; McGlynn, Angela P; McNulty, Helene; O'Reilly, Sharleen L; McKelvey-Martin, Valerie; McKerr, George; Strain, JJ; Scott, John; Downes, Stephen.

In: Journal of Nutrition, Vol. 136, No. 11, 11.2006, p. 2748-2753.

Research output: Contribution to journalArticle

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T1 - Global DNA and p53 region-specific hypomethylation in human colonic cells is induced by folate depletion and reversed by folate supplementation

AU - Wasson, Gillian R

AU - McGlynn, Angela P

AU - McNulty, Helene

AU - O'Reilly, Sharleen L

AU - McKelvey-Martin, Valerie

AU - McKerr, George

AU - Strain, JJ

AU - Scott, John

AU - Downes, Stephen

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N2 - There is increasing evidence to suggest that reduced folate status may be a causative factor in carcinogenesis, particularly colorectal carcinogenesis. Folate is essential for the synthesis of S-adenosylmethionine, the methyl donor required for all methylation reactions in the cell, including the methylation of DNA. Global DNA hypomethylation appears to be an early, and consistent, molecular event in carcinogenesis. We have examined the effects of folate depletion on human-derived cultured colon carcinoma cells using 2 novel modifications to the Comet (single cell gel electrophoresis) assay to detect global DNA hypomethylation and gene region-specific DNA hypomethylation. Colon cells cultured in folate-free medium for 14 d showed a significant increase in global DNA hypomethylation compared with cells grown in medium containing 3 mu mol/L folic acid. This was also true at a gene level, with folate-deprived cells showing significantly more DNA hypomethylation in the region of the p53 gene. In both cases, the effects of folate depletion were completely reversed by the reintroduction of folic acid to the cells. These results confirm that decreased folate levels are capable of inducing DNA hypomethylation in colon cells and particularly in the region of the p53 gene, suggesting that a more optimal folate status in vivo may normalize any DNA hypomethylation, offering potential protective effects against carcinogenesis. This study also introduces 2 novel functional biomarkers of DNA hypomethylation and demonstrates their suitability to detect folate depletion-induced molecular changes.

AB - There is increasing evidence to suggest that reduced folate status may be a causative factor in carcinogenesis, particularly colorectal carcinogenesis. Folate is essential for the synthesis of S-adenosylmethionine, the methyl donor required for all methylation reactions in the cell, including the methylation of DNA. Global DNA hypomethylation appears to be an early, and consistent, molecular event in carcinogenesis. We have examined the effects of folate depletion on human-derived cultured colon carcinoma cells using 2 novel modifications to the Comet (single cell gel electrophoresis) assay to detect global DNA hypomethylation and gene region-specific DNA hypomethylation. Colon cells cultured in folate-free medium for 14 d showed a significant increase in global DNA hypomethylation compared with cells grown in medium containing 3 mu mol/L folic acid. This was also true at a gene level, with folate-deprived cells showing significantly more DNA hypomethylation in the region of the p53 gene. In both cases, the effects of folate depletion were completely reversed by the reintroduction of folic acid to the cells. These results confirm that decreased folate levels are capable of inducing DNA hypomethylation in colon cells and particularly in the region of the p53 gene, suggesting that a more optimal folate status in vivo may normalize any DNA hypomethylation, offering potential protective effects against carcinogenesis. This study also introduces 2 novel functional biomarkers of DNA hypomethylation and demonstrates their suitability to detect folate depletion-induced molecular changes.

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