Short-term dietary methionine supplementation affects one-carbon metabolism and DNA methylation in the mouse gut and leads to altered microbiome profiles, barrier function, gene expression and histomorphology

ABSTRACT Epigenetic alterations, such as those linked to DNA methylation, may potentially provide molecular explanations for complications associated with altered gene expression in illnesses, such as chronic kidney disease (CKD). Although both DNA hypo- and hypermethylation have been observed in the uremic milieu, this remains only a single aspect of the epigenetic landscape and, thus, of any biochemical dysregulation associated with CKD. Nevertheless, the role of uremia-promoting alterations on the epigenetic landscape regulating gene expression is still a novel and scarcely studied field. Although few studies have actually reported alterations of DNA methylation via methyl donor nutrient intake, emerging evidence indicates that nutritional modification of the microbiome can affect one-carbon metabolism and the capacity to methylate the genome in CKD. In this review, we discuss the nutritional modifications that may affect one-carbon metabolism and the possible impact of methyl donor nutrients on the microbiome, CKD, and its phenotype.

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Uteroplacental insufficiency alters DNA methylation, one-carbon metabolism, and histone acetylation in IUGR rats

Physiological Genomics ◽

10.1152/physiolgenomics.00042.2004 ◽

2004 ◽

Vol 18 (1) ◽

pp. 43-50 ◽

Cited By ~ 155

Author(s):

Nicole K. MacLennan ◽

S. Jill James ◽

Stephan Melnyk ◽

Ali Piroozi ◽

Stefanie Jernigan ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Histone Acetylation ◽

Carbon Metabolism ◽

Hepatic Gene Expression ◽

Mrna Levels ◽

Dna Hypomethylation ◽

Artery Ligation ◽

Transient Nature ◽

One Carbon Metabolism

Uteroplacental insufficiency leads to intrauterine growth retardation (IUGR) and increases the risk of insulin resistance and hypertriglyceridemia in both humans and rats. Postnatal changes in hepatic gene expression characterize the postnatal IUGR rat, despite the transient nature of the initial in utero insult. Phenomena such as DNA methylation and histone acetylation can induce a relatively static reprogramming of gene transcription by altering chromatin infrastructure. We therefore hypothesized that uteroplacental insufficiency persistently affects DNA methylation and histone acetylation in the IUGR rat liver. IUGR rat pups were created by inducing uteroplacental insufficiency through bilateral uterine artery ligation of the pregnant dam on day 19 of gestation. The SssI methyltransferase assay and two-dimensional thin-layer chromatography demonstrated genome-wide DNA hypomethylation in postnatal IUGR liver. To investigate a possible mechanism for this hypomethylation, levels of hepatic metabolites and enzyme mRNAs involved in one-carbon metabolism were measured using HPLC with coulometric electrochemical detection and real-time RT-PCR, respectively. Uteroplacental insufficiency increased IUGR levels of S-adenosylhomocysteine, homocysteine, and methionine in association with decreased mRNA levels of methionine adenosyltransferase and cystathionine-β-synthase. Western blotting further demonstrated that increased quantities of acetylated histone H3 also characterized the IUGR liver. Increased hepatic levels of S-adenosylhomocysteine can promote DNA hypomethylation, which is often associated with histone hyperacetylation. We speculate that the altered intrauterine milieu associated with uteroplacental insufficiency affects hepatic one-carbon metabolism and subsequent DNA methylation, which thereby alters chromatin dynamics and leads to persistent changes in hepatic gene expression.

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Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism

Oncogene ◽

10.1038/onc.2017.367 ◽

2017 ◽

Vol 37 (7) ◽

pp. 963-970 ◽

Cited By ~ 44

Author(s):

E Cuyàs ◽

S Fernández-Arroyo ◽

S Verdura ◽

R Á-F García ◽

J Stursa ◽

...

Keyword(s):

Dna Methylation ◽

Carbon Metabolism ◽

Global Dna Methylation ◽

One Carbon Metabolism

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Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

International Journal of Molecular Sciences ◽

10.3390/ijms19103106 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3106 ◽

Cited By ~ 19

Author(s):

Kuniyasu Soda

Keyword(s):

Dna Methylation ◽

Carbon Metabolism ◽

Methylation Status ◽

Significant Risk ◽

Significant Risk Factor ◽

Dna Methyltransferases ◽

Polyamine Metabolism ◽

Methyl Group ◽

Wide Range ◽

One Carbon Metabolism

Recent investigations have revealed that changes in DNA methylation status play an important role in aging-associated pathologies and lifespan. The methylation of DNA is regulated by DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) in the presence of S-adenosylmethionine (SAM), which serves as a methyl group donor. Increased availability of SAM enhances DNMT activity, while its metabolites, S-adenosyl-l-homocysteine (SAH) and decarboxylated S-adenosylmethionine (dcSAM), act to inhibit DNMT activity. SAH, which is converted from SAM by adding a methyl group to cytosine residues in DNA, is an intermediate precursor of homocysteine. dcSAM, converted from SAM by the enzymatic activity of adenosylmethionine decarboxylase, provides an aminopropyl group to synthesize the polyamines spermine and spermidine. Increased homocysteine levels are a significant risk factor for the development of a wide range of conditions, including cardiovascular diseases. However, successful homocysteine-lowering treatment by vitamins (B6, B12, and folate) failed to improve these conditions. Long-term increased polyamine intake elevated blood spermine levels and inhibited aging-associated pathologies in mice and humans. Spermine reversed changes (increased dcSAM, decreased DNMT activity, aberrant DNA methylation, and proinflammatory status) induced by the inhibition of ornithine decarboxylase. The relation between polyamine metabolism, one-carbon metabolism, DNA methylation, and the biological mechanism of spermine-induced lifespan extension is discussed.

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Association between one-carbon metabolism indices and DNA methylation status in maternal and cord blood

Scientific Reports ◽

10.1038/s41598-018-35111-1 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 5

Author(s):

Anna K. Knight ◽

Hea Jin Park ◽

Dorothy B. Hausman ◽

Jennifer M. Fleming ◽

Victoria L. Bland ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Carbon Metabolism ◽

Methylation Status ◽

One Carbon Metabolism

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Caffeine induces both short‐term and long‐term effects on gene expression and DNA methylation in the mouse heart (542.3)

The FASEB Journal ◽

10.1096/fasebj.28.1_supplement.542.3 ◽

2014 ◽

Vol 28 (S1) ◽

Author(s):

Christopher Wendler ◽

Ryan Poulsen ◽

Xiefan Fang

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Mouse Heart ◽

Long Term Effects ◽

Short Term

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Modeling folate, one-carbon metabolism, and DNA methylation

Nutrition Reviews ◽

10.1111/j.1753-4887.2008.00062.x ◽

2008 ◽

Vol 66 ◽

pp. S27-S30 ◽

Cited By ~ 35

Author(s):

Cornelia M Ulrich ◽

Michael C Reed ◽

H Frederik Nijhout

Keyword(s):

Dna Methylation ◽

Carbon Metabolism ◽

One Carbon Metabolism

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dysregulates hepatic one carbon metabolism during the progression of steatosis to steatohepatitis with fibrosis in mice

Scientific Reports ◽

10.1038/s41598-020-71795-0 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Russell R. Fling ◽

Claire M. Doskey ◽

Kelly A. Fader ◽

Rance Nault ◽

Tim R. Zacharewski

Keyword(s):

Gene Expression ◽

Carbon Metabolism ◽

Fatty Liver Disease ◽

Bolus Dose ◽

Alcoholic Fatty Liver ◽

Homocysteic Acid ◽

Protein Levels ◽

One Carbon Metabolism ◽

Dose Dependent ◽

Alcoholic Fatty Liver Disease

Abstract 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a persistent environmental contaminant, induces steatosis that can progress to steatohepatitis with fibrosis, pathologies that parallel stages in the development of non-alcoholic fatty liver disease (NAFLD). Coincidently, one carbon metabolism (OCM) gene expression and metabolites are often altered during NAFLD progression. In this study, the time- and dose-dependent effects of TCDD were examined on hepatic OCM in mice. Despite AhR ChIP-seq enrichment at 2 h, OCM gene expression was not changed within 72 h following a bolus dose of TCDD. Dose-dependent repression of methionine adenosyltransferase 1A (Mat1a), adenosylhomocysteinase (Achy) and betaine-homocysteine S-methyltransferase (Bhmt) mRNA and protein levels following repeated treatments were greater at 28 days compared to 8 days. Accordingly, levels of methionine, betaine, and homocysteic acid were dose-dependently increased, while S-adenosylmethionine, S-adenosylhomocysteine, and cystathionine exhibited non-monotonic dose-dependent responses consistent with regulation by OCM intermediates and repression of glycine N-methyltransferase (Gnmt). However, the dose-dependent effects on SAM-dependent metabolism of polyamines and creatine could not be directly attributed to alterations in SAM levels. Collectively, these results demonstrate persistent AhR activation disrupts hepatic OCM metabolism at the transcript, protein and metabolite levels within context of TCDD-elicited progression of steatosis to steatohepatitis with fibrosis.

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