Effect of folic acid supplementation on genomic DNA methylation in patients with colorectal adenoma

Abstract

Background and aims: A low dietary folate intake can cause genomic DNA hypomethylation and may increase the risk of colorectal neoplasia. The hypothesis that folic acid supplementation increases DNA methylation in leucocytes and colorectal mucosa was tested in 31 patients with histologically confirmed colorectal adenoma using a randomised, double blind, placebo controlled, parallel design. Methods: Subjects were randomised to receive either 400 mg/day folic acid supplement (n = 15) or placebo (n = 16) for 10 weeks. Genomic DNA methylation, serum and erythrocyte folate, and plasma homocysteine concentrations were measured at baseline and post intervention. Results: Folic acid supplementation increased serum and erythrocyte folate concentrations by 81% (95% confidence interval (CI) 57-104%; p,0.001 v placebo) and 57% (95% CI 40-74%; p,0.001 v placebo), respectively, and decreased plasma homocysteine concentration by 12% (95% CI 4-20%; p = 0.01 v placebo). Folic acid supplementation resulted in increases in DNA methylation of 31% (95% CI 16-47%; p = 0.05 v placebo) in leucocytes and 25% (95% CI 11-39%; p = 0.09 v placebo) in colonic mucosa. Conclusions: These results suggest that DNA hypomethylation can be reversed by physiological intakes of folic acid.

Methionine transmethylation and transsulfuration in the piglet gastrointestinal tract

“…Genetic defects in methionine metabolism related to methionine synthase, N 5,10 -methylenetetrahyrdofolate, also result in neural dysfunction, mental retardation, and pregnancy complications (6)(7)(8). Recent studies have linked homocysteine, folate, and DNA methylation with gastrointestinal diseases, namely inflammatory bowel disease and colon cancer (9)(10)(11)(12)(13). The underlying mechanism linking homocysteine to inflammatory disease may be the induction of leukocyte adhesion molecules and proinflammatory cytokines in vascular endothelial cells (10).…”

A new perspective on neural tube defects: Folic acid and microRNA misexpression

“…Although DHFR did not turn up any significant hits in the database search and miR-24 was not considered an miRNA of interest in this review (neither it is neural specific nor was it predicted to target Dll1, Dnmt1, Mthfr, or Rbl2), Mishra et al, 2004. showed that DHFR is targeted by miR-24, which was found to be upregulated 1.36 times greater than control in TK-6 cells grown in FAD media (Marsit et al, 2006). This suggests that folate deficiency could initiate a negative feedback loop where overexpression of miR-24 suppresses DHFR, which would further decrease methyl-donor pools, exacerbating methyl deficiency (Bohnsack and Hirschi, 2004;Pufulete et al, 2005;Fig. 4).…”

“…The precursor cells for both neural crest cells and the neuroepithelial cells of the neural tube also have a higher level of folate receptor expression (Boot et al, 2003). Research has shown that folic acid levels directly correlate to genomic DNA methylation and deficiency is associated with global genomic hypomethylation, which is reversible with repletion therapy (Bohnsack and Hirschi, 2004;Choi et al, 2005;Pufulete et al, 2005;Rampersaud et al, 2000).…”

“…If homocysteine is not converted to methionine then it may be converted back to SAH, which inhibits DNA methyltransferases because they have an increased affinity for SAH over SAM (Jackson et al, 2004). Cystathione-b-synthase (CBS) is the first enzyme of the transsulfuration pathway that irreversibly removes cellular homocysteine; in the CBS knockout mouse model, increased levels of SAH leads to genomic DNA hypomethylation (Pufulete et al, 2005). Rosenquist et al were able to produce NTDs and cardiac abnormalities by the addition of homocysteine to developing chick embryos.…”

“…An increase in miR-34a may lead to a decrease in MTHFR expression, which in turn would lead to a decrease in the level of 5-methyl-THF (Bohnsack and Hirschi, 2004;Pufulete et al, 2005;Fig. 4).…”