A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status

DNA methylation, an essential epigenetic feature of DNA that modulates gene expression and genomic integrity, is catalyzed by methyltransferases that use the universal methyl donor S-adenosyl-l-methionine. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolat...

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Vydáno v:	Proceedings of the National Academy of Sciences - PNAS Ročník 99; číslo 8; s. 5606
Hlavní autoři:	Friso, Simonetta, Choi, Sang-Woon, Girelli, Domenico, Mason, Joel B, Dolnikowski, Gregory G, Bagley, Pamela J, Olivieri, Oliviero, Jacques, Paul F, Rosenberg, Irwin H, Corrocher, Roberto, Selhub, Jacob
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 16.04.2002
Témata:	Adult Aged Coronary Artery Disease - genetics DNA Methylation Female Folic Acid - blood Genotype Homozygote Humans Male Mass Spectrometry Methylenetetrahydrofolate Dehydrogenase (NAD+) Methylenetetrahydrofolate Reductase (NADPH2) Middle Aged Models, Statistical Mutation Oxidoreductases - genetics Oxidoreductases Acting on CH-NH Group Donors - genetics Polymorphism, Genetic
ISSN:	0027-8424
On-line přístup:	Zjistit podrobnosti o přístupu
Tagy:	Přidat tag Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!

Abstract	DNA methylation, an essential epigenetic feature of DNA that modulates gene expression and genomic integrity, is catalyzed by methyltransferases that use the universal methyl donor S-adenosyl-l-methionine. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), the methyl donor for synthesis of methionine from homocysteine and precursor of S-adenosyl-l-methionine. In the present study we sought to determine the effect of folate status on genomic DNA methylation with an emphasis on the interaction with the common C677T mutation in the MTHFR gene. A liquid chromatography/MS method for the analysis of nucleotide bases was used to assess genomic DNA methylation in peripheral blood mononuclear cell DNA from 105 subjects homozygous for this mutation (T/T) and 187 homozygous for the wild-type (C/C) MTHFR genotype. The results show that genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine (tHcy) levels (P < 0.01). T/T genotypes had a diminished level of DNA methylation compared with those with the C/C wild-type (32.23 vs.62.24 ng 5-methylcytosine/microg DNA, P < 0.0001). When analyzed according to folate status, however, only the T/T subjects with low levels of folate accounted for the diminished DNA methylation (P < 0.0001). Moreover, in T/T subjects DNA methylation status correlated with the methylated proportion of red blood cell folate and was inversely related to the formylated proportion of red blood cell folates (P < 0.03) that is known to be solely represented in those individuals. These results indicate that the MTHFR C677T polymorphism influences DNA methylation status through an interaction with folate status.
AbstractList	DNA methylation, an essential epigenetic feature of DNA that modulates gene expression and genomic integrity, is catalyzed by methyltransferases that use the universal methyl donor S-adenosyl-l-methionine. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), the methyl donor for synthesis of methionine from homocysteine and precursor of S-adenosyl-l-methionine. In the present study we sought to determine the effect of folate status on genomic DNA methylation with an emphasis on the interaction with the common C677T mutation in the MTHFR gene. A liquid chromatography/MS method for the analysis of nucleotide bases was used to assess genomic DNA methylation in peripheral blood mononuclear cell DNA from 105 subjects homozygous for this mutation (T/T) and 187 homozygous for the wild-type (C/C) MTHFR genotype. The results show that genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine (tHcy) levels (P < 0.01). T/T genotypes had a diminished level of DNA methylation compared with those with the C/C wild-type (32.23 vs.62.24 ng 5-methylcytosine/microg DNA, P < 0.0001). When analyzed according to folate status, however, only the T/T subjects with low levels of folate accounted for the diminished DNA methylation (P < 0.0001). Moreover, in T/T subjects DNA methylation status correlated with the methylated proportion of red blood cell folate and was inversely related to the formylated proportion of red blood cell folates (P < 0.03) that is known to be solely represented in those individuals. These results indicate that the MTHFR C677T polymorphism influences DNA methylation status through an interaction with folate status. DNA methylation, an essential epigenetic feature of DNA that modulates gene expression and genomic integrity, is catalyzed by methyltransferases that use the universal methyl donor S-adenosyl-l-methionine. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), the methyl donor for synthesis of methionine from homocysteine and precursor of S-adenosyl-l-methionine. In the present study we sought to determine the effect of folate status on genomic DNA methylation with an emphasis on the interaction with the common C677T mutation in the MTHFR gene. A liquid chromatography/MS method for the analysis of nucleotide bases was used to assess genomic DNA methylation in peripheral blood mononuclear cell DNA from 105 subjects homozygous for this mutation (T/T) and 187 homozygous for the wild-type (C/C) MTHFR genotype. The results show that genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine (tHcy) levels (P < 0.01). T/T genotypes had a diminished level of DNA methylation compared with those with the C/C wild-type (32.23 vs.62.24 ng 5-methylcytosine/microg DNA, P < 0.0001). When analyzed according to folate status, however, only the T/T subjects with low levels of folate accounted for the diminished DNA methylation (P < 0.0001). Moreover, in T/T subjects DNA methylation status correlated with the methylated proportion of red blood cell folate and was inversely related to the formylated proportion of red blood cell folates (P < 0.03) that is known to be solely represented in those individuals. These results indicate that the MTHFR C677T polymorphism influences DNA methylation status through an interaction with folate status.DNA methylation, an essential epigenetic feature of DNA that modulates gene expression and genomic integrity, is catalyzed by methyltransferases that use the universal methyl donor S-adenosyl-l-methionine. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), the methyl donor for synthesis of methionine from homocysteine and precursor of S-adenosyl-l-methionine. In the present study we sought to determine the effect of folate status on genomic DNA methylation with an emphasis on the interaction with the common C677T mutation in the MTHFR gene. A liquid chromatography/MS method for the analysis of nucleotide bases was used to assess genomic DNA methylation in peripheral blood mononuclear cell DNA from 105 subjects homozygous for this mutation (T/T) and 187 homozygous for the wild-type (C/C) MTHFR genotype. The results show that genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine (tHcy) levels (P < 0.01). T/T genotypes had a diminished level of DNA methylation compared with those with the C/C wild-type (32.23 vs.62.24 ng 5-methylcytosine/microg DNA, P < 0.0001). When analyzed according to folate status, however, only the T/T subjects with low levels of folate accounted for the diminished DNA methylation (P < 0.0001). Moreover, in T/T subjects DNA methylation status correlated with the methylated proportion of red blood cell folate and was inversely related to the formylated proportion of red blood cell folates (P < 0.03) that is known to be solely represented in those individuals. These results indicate that the MTHFR C677T polymorphism influences DNA methylation status through an interaction with folate status.
Author	Corrocher, Roberto Girelli, Domenico Mason, Joel B Dolnikowski, Gregory G Jacques, Paul F Selhub, Jacob Olivieri, Oliviero Friso, Simonetta Choi, Sang-Woon Bagley, Pamela J Rosenberg, Irwin H
Author_xml	– sequence: 1 givenname: Simonetta surname: Friso fullname: Friso, Simonetta organization: Vitamin Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA – sequence: 2 givenname: Sang-Woon surname: Choi fullname: Choi, Sang-Woon – sequence: 3 givenname: Domenico surname: Girelli fullname: Girelli, Domenico – sequence: 4 givenname: Joel B surname: Mason fullname: Mason, Joel B – sequence: 5 givenname: Gregory G surname: Dolnikowski fullname: Dolnikowski, Gregory G – sequence: 6 givenname: Pamela J surname: Bagley fullname: Bagley, Pamela J – sequence: 7 givenname: Oliviero surname: Olivieri fullname: Olivieri, Oliviero – sequence: 8 givenname: Paul F surname: Jacques fullname: Jacques, Paul F – sequence: 9 givenname: Irwin H surname: Rosenberg fullname: Rosenberg, Irwin H – sequence: 10 givenname: Roberto surname: Corrocher fullname: Corrocher, Roberto – sequence: 11 givenname: Jacob surname: Selhub fullname: Selhub, Jacob
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/11929966$$D View this record in MEDLINE/PubMed
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Snippet	DNA methylation, an essential epigenetic feature of DNA that modulates gene expression and genomic integrity, is catalyzed by methyltransferases that use the...
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SubjectTerms	Adult Aged Coronary Artery Disease - genetics DNA Methylation Female Folic Acid - blood Genotype Homozygote Humans Male Mass Spectrometry Methylenetetrahydrofolate Dehydrogenase (NAD+) Methylenetetrahydrofolate Reductase (NADPH2) Middle Aged Models, Statistical Mutation Oxidoreductases - genetics Oxidoreductases Acting on CH-NH Group Donors - genetics Polymorphism, Genetic
Title	A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status
URI	https://www.ncbi.nlm.nih.gov/pubmed/11929966 https://www.proquest.com/docview/71624456
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