Riboflavin supplementation alters global and gene-specific DNA methylation in adults with the MTHFR 677 TT genotype

Sophia Amenyah; A McMahon; M Ward; Jennifer Deane; H McNulty; Catherine Hughes; J.J. Strain; Geraldine Horigan; J Purvis; CP Walsh; Diane Lees Murdock

doi:10.1016/j.biochi.2020.04.007

Riboflavin supplementation alters global and gene-specific DNA methylation in adults with the MTHFR 677 TT genotype

Sophia Amenyah, A McMahon, M Ward, Jennifer Deane, H McNulty, Catherine Hughes, J.J. Strain, Geraldine Horigan, J Purvis, CP Walsh, Diane Lees Murdock

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Abstract

DNA methylation is important in regulating gene expression and genomic stability while aberrant DNA methylation is associated with disease. Riboflavin (FAD) is a cofactor for methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate recycling, which generates methyl groups for homocysteine remethylation to methionine, the pre-cursor to the universal methyl donor S-adenosylmethionine (SAM). A polymorphism (C677T) in MTHFR results in decreased MTHFR activity and increased homocysteine concentration. Previous studies demonstrated that riboflavin modulates this phenotype in homozygous adults (MTHFR 677 TT genotype), however, DNA methylation was not considered. This study examined DNA methylation, globally and at key MTHFR regulatory sites, in adults stratified by MTHFR genotype and the effect of riboflavin supplementation on DNA methylation in individuals with the 677 TT genotype. Samples were accessed from participants, screened for the MTHFR C677T polymorphism, who participated in observational (n = 80) and targeted riboflavin (1.6 mg/day) RCTs (n = 80). DNA methylation at LINE-1 and key regulatory regions of the MTHFR locus were analysed by pyrosequencing in peripheral blood leukocytes. LINE-1 (+1.6%; p = 0.011) and MTHFR south shelf (+4.7%, p < 0.001) were significantly hypermethylated in individuals with the MTHFR 677 TT compared to CC genotype. Riboflavin supplementation resulted in decreased global methylation, albeit only significant at one CpG. A significant reduction in DNA methylation at the MTHFR north shore (−1.2%, p < 0.001) was also observed in TT adults following intervention with riboflavin. This provides the first RCT evidence that DNA methylation may be modulated by riboflavin in adults with the MTHFR 677 TT genotype.

Original language	English
Pages (from-to)	17-26
Number of pages	10
Journal	Biochimie
Volume	173
Early online date	22 Apr 2020
DOIs	https://doi.org/10.1016/j.biochi.2020.04.007
Publication status	Published (in print/issue) - 1 Jun 2020

Bibliographical note

Funding Information:
This work was funded by grants from Northern Ireland Chest, Heart and Stroke Association ( NICHS206_07 ; DLM & MW), DSM Nutritional Products (MW, HN, JJS and CH), ESRC / BBSRC (ES /N000323/1;CPW, HN & DLM). Sophia D. Amenyah was supported by a Vice Chancellor’s Research Scholarship from Ulster University. The funding organisations had no role, in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Publisher Copyright:
© 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM)

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Keywords

DNA methylation
riboflavin
MTHFR C677T polymorphism
one-carbon metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.biochi.2020.04.007

Amenyah et al_ManuscriptBiochimie 2020_20052020Author Accepted Manuscript, 819 KB

Cite this

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title = "Riboflavin supplementation alters global and gene-specific DNA methylation in adults with the MTHFR 677 TT genotype",

abstract = "DNA methylation is important in regulating gene expression and genomic stability while aberrant DNA methylation is associated with disease. Riboflavin (FAD) is a cofactor for methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate recycling, which generates methyl groups for homocysteine remethylation to methionine, the pre-cursor to the universal methyl donor S-adenosylmethionine (SAM). A polymorphism (C677T) in MTHFR results in decreased MTHFR activity and increased homocysteine concentration. Previous studies demonstrated that riboflavin modulates this phenotype in homozygous adults (MTHFR 677 TT genotype), however, DNA methylation was not considered. This study examined DNA methylation, globally and at key MTHFR regulatory sites, in adults stratified by MTHFR genotype and the effect of riboflavin supplementation on DNA methylation in individuals with the 677 TT genotype. Samples were accessed from participants, screened for the MTHFR C677T polymorphism, who participated in observational (n = 80) and targeted riboflavin (1.6 mg/day) RCTs (n = 80). DNA methylation at LINE-1 and key regulatory regions of the MTHFR locus were analysed by pyrosequencing in peripheral blood leukocytes. LINE-1 (+1.6%; p = 0.011) and MTHFR south shelf (+4.7%, p < 0.001) were significantly hypermethylated in individuals with the MTHFR 677 TT compared to CC genotype. Riboflavin supplementation resulted in decreased global methylation, albeit only significant at one CpG. A significant reduction in DNA methylation at the MTHFR north shore (−1.2%, p < 0.001) was also observed in TT adults following intervention with riboflavin. This provides the first RCT evidence that DNA methylation may be modulated by riboflavin in adults with the MTHFR 677 TT genotype.",

keywords = "DNA methylation, riboflavin, MTHFR C677T polymorphism, one-carbon metabolism",

author = "Sophia Amenyah and A McMahon and M Ward and Jennifer Deane and H McNulty and Catherine Hughes and J.J. Strain and Geraldine Horigan and J Purvis and CP Walsh and {Lees Murdock}, Diane",

note = "Funding Information: This work was funded by grants from Northern Ireland Chest, Heart and Stroke Association ( NICHS206_07 ; DLM & MW), DSM Nutritional Products (MW, HN, JJS and CH), ESRC / BBSRC (ES /N000323/1;CPW, HN & DLM). Sophia D. Amenyah was supported by a Vice Chancellor{\textquoteright}s Research Scholarship from Ulster University. The funding organisations had no role, in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Publisher Copyright: {\textcopyright} 2020 Elsevier B.V. and Soci{\'e}t{\'e} Fran{\c c}aise de Biochimie et Biologie Mol{\'e}culaire (SFBBM) Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

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AU - Amenyah, Sophia

AU - McMahon, A

AU - Ward, M

AU - Deane, Jennifer

AU - McNulty, H

AU - Hughes, Catherine

AU - Strain, J.J.

AU - Horigan, Geraldine

AU - Purvis, J

AU - Walsh, CP

AU - Lees Murdock, Diane

N1 - Funding Information: This work was funded by grants from Northern Ireland Chest, Heart and Stroke Association ( NICHS206_07 ; DLM & MW), DSM Nutritional Products (MW, HN, JJS and CH), ESRC / BBSRC (ES /N000323/1;CPW, HN & DLM). Sophia D. Amenyah was supported by a Vice Chancellor’s Research Scholarship from Ulster University. The funding organisations had no role, in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Publisher Copyright: © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM) Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/6/1

Y1 - 2020/6/1

N2 - DNA methylation is important in regulating gene expression and genomic stability while aberrant DNA methylation is associated with disease. Riboflavin (FAD) is a cofactor for methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate recycling, which generates methyl groups for homocysteine remethylation to methionine, the pre-cursor to the universal methyl donor S-adenosylmethionine (SAM). A polymorphism (C677T) in MTHFR results in decreased MTHFR activity and increased homocysteine concentration. Previous studies demonstrated that riboflavin modulates this phenotype in homozygous adults (MTHFR 677 TT genotype), however, DNA methylation was not considered. This study examined DNA methylation, globally and at key MTHFR regulatory sites, in adults stratified by MTHFR genotype and the effect of riboflavin supplementation on DNA methylation in individuals with the 677 TT genotype. Samples were accessed from participants, screened for the MTHFR C677T polymorphism, who participated in observational (n = 80) and targeted riboflavin (1.6 mg/day) RCTs (n = 80). DNA methylation at LINE-1 and key regulatory regions of the MTHFR locus were analysed by pyrosequencing in peripheral blood leukocytes. LINE-1 (+1.6%; p = 0.011) and MTHFR south shelf (+4.7%, p < 0.001) were significantly hypermethylated in individuals with the MTHFR 677 TT compared to CC genotype. Riboflavin supplementation resulted in decreased global methylation, albeit only significant at one CpG. A significant reduction in DNA methylation at the MTHFR north shore (−1.2%, p < 0.001) was also observed in TT adults following intervention with riboflavin. This provides the first RCT evidence that DNA methylation may be modulated by riboflavin in adults with the MTHFR 677 TT genotype.

AB - DNA methylation is important in regulating gene expression and genomic stability while aberrant DNA methylation is associated with disease. Riboflavin (FAD) is a cofactor for methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate recycling, which generates methyl groups for homocysteine remethylation to methionine, the pre-cursor to the universal methyl donor S-adenosylmethionine (SAM). A polymorphism (C677T) in MTHFR results in decreased MTHFR activity and increased homocysteine concentration. Previous studies demonstrated that riboflavin modulates this phenotype in homozygous adults (MTHFR 677 TT genotype), however, DNA methylation was not considered. This study examined DNA methylation, globally and at key MTHFR regulatory sites, in adults stratified by MTHFR genotype and the effect of riboflavin supplementation on DNA methylation in individuals with the 677 TT genotype. Samples were accessed from participants, screened for the MTHFR C677T polymorphism, who participated in observational (n = 80) and targeted riboflavin (1.6 mg/day) RCTs (n = 80). DNA methylation at LINE-1 and key regulatory regions of the MTHFR locus were analysed by pyrosequencing in peripheral blood leukocytes. LINE-1 (+1.6%; p = 0.011) and MTHFR south shelf (+4.7%, p < 0.001) were significantly hypermethylated in individuals with the MTHFR 677 TT compared to CC genotype. Riboflavin supplementation resulted in decreased global methylation, albeit only significant at one CpG. A significant reduction in DNA methylation at the MTHFR north shore (−1.2%, p < 0.001) was also observed in TT adults following intervention with riboflavin. This provides the first RCT evidence that DNA methylation may be modulated by riboflavin in adults with the MTHFR 677 TT genotype.

KW - DNA methylation

KW - riboflavin

KW - MTHFR C677T polymorphism

KW - one-carbon metabolism

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JO - Biochimie

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Riboflavin supplementation alters global and gene-specific DNA methylation in adults with the MTHFR 677 TT genotype

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

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Epigenetic effects of riboflavin supplementation on hypertension in adults screened for the MTHFR C677T polymorphism

Cite this

Riboflavin supplementation alters global and gene-specific DNA methylation in adults with the MTHFR 677 TT genotype

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Student theses

Epigenetic effects of riboflavin supplementation on hypertension in adults screened for the MTHFR C677T polymorphism

Cite this