Abstract
DNA methylation regulates gene expression and can be modified by different bioactive compounds in foods, such as polyphenols. Cocoa is a rich source of polyphenols, but its role in DNA methylation is still unknown. The objective was to assess the effect of cocoa consumption on DNA methylation and to determine whether the enzymes involved in the DNA methylation process participate in the mechanisms by which cocoa exerts these effects in humans. The global DNA methylation levels in the peripheral blood were evaluated in 214 volunteers who were pre-hypertensive, stage-1 hypertensive or hypercholesterolemic. The volunteers were divided into two groups: 110 subjects who consumed cocoa (6 g/d) for two weeks and 104 control subjects. In addition, the peripheral blood mononuclear cells (PBMCs) from six subjects were treated with a cocoa extract to analyze the mRNA levels of the DNA methyltransferases (DNMTs), methylenetetrahydrofolate reductase (MTHFR), and methionine synthase reductase (MTRR) genes. Cocoa consumption significantly reduced the DNA methylation levels (2.991±0.366 vs. 3.909±0.380, p<0.001). Additionally, we found an association between the cocoa effects on DNA methylation and three polymorphisms located in the MTHFR, MTRR, and DNMT3B genes. Furthermore, in PBMCs, the cocoa extract significantly lowered the mRNA levels of the DNMTs, MTHFR, and MTRR. Our study demonstrates for the first time that the consumption of cocoa decreases the global DNA methylation of peripheral leukocytes in humans with cardiovascular risk factors. In vitro experiments with PBMCs suggest that cocoa may exert this effect partially via the down-regulation of DNMTs, MTHFR and MTRR, which are key genes involved in this epigenetic process.Trial Registration Clinicaltrials.gov NCT00511420 and NCT00502047
Highlights
DNA methylation is a major epigenetic process that regulates gene expression and chromatin architecture
We evaluated in vitro the effect of a cocoa polyphenol extract treatment on the mRNA expression levels of these five genes related to the DNA methylation pathway (DNMT1, DNMT3a, DNMT3b, methylenetetrahydrofolate reductase (MTHFR) and MTRR) using peripheral blood mononuclear cells (PBMCs) from humans
The results of the present study demonstrate that cocoa consumption causes alterations in the global DNA methylation of peripheral leukocytes in humans with cardiovascular risk factors, lowering the %5mC levels
Summary
DNA methylation is a major epigenetic process that regulates gene expression and chromatin architecture. DNA methylation occurs primarily at the 59 position of the cytosine residues within cytosine-guanine (CpG) dinucleotides and involves the addition of a methyl group to form 5-methylcytosine (5mC) [1]. This epigenetic process is catalyzed by specific DNA methyltransferases (DNMTs). There are three main DNMTs. DNMT1 is the major maintenance enzyme that preserves existing methylation patterns following DNA replication; DNMT3a and DNMT3b, in contrast, are primarily responsible for the formation of de novo DNA methylation patterns [1,2]. Other enzymes, such as the folate metabolizing enzymes methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), play an important role in DNA methylation by influencing the bioavailability of methyl groups [3,4]
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