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Epicatechin metabolites exert epigenetic regulation in endothelial cells by modulating DNA methylation profile

ABSTRACT: Diets rich in flavanols are known to exert beneficial cardiovascular health effects. We previously showed that epicatechin metabolites reduce monocyte-endothelial cell adhesion by modulating expression of genes in HUVECs involved in cell adhesion signaling pathways. The aim of the present study is to examine potential epigenetic remodeling of HUVEC cells upon inflammation in presence or absence of cocoa derived epicatechin metabolites through genomewide DNA methylation profiling. Epicatechin metabolites were found to trigger DNA hypermethylation in gene bodies and intergenic genomic regions, while hypomethylation in promoter regions. In addition, pathway enrichment of differentially methylated genes demonstrates epigenetic remodeling cell adhesion and cytoskeleton signaling pathways. Finally, in silico docking supports evidence for direct regulation of DNMTs through epicatechin binding. In conclusion, our study provides evidence that epicatechin metabolites elicit vascular health effects in part through epigenetic regulation of endothelial cell adhesion functions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133418 | GEO | 2019/12/31

REPOSITORIES: GEO

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Project description:Background: In a recent intervention study, the daily supplementation with 200 mg monomeric and oligomeric flavanols (MOF) from grape seeds for 8 weeks revealed a vascular health benefit in male smokers. The objective of the present study was to determine the impact of MOF consumption on the gene expression profile of leukocytes and to assess changes in DNA methylation. Methodology/Principal Findings: Gene expression profiles were determined using whole genome microarrays (Agilent) and DNA methylation was assessed using HumanMethylation450 BeadChips (Illumina). MOF significantly modulated the expression of 864 genes. The majority of the affected genes are involved in chemotaxis, cell adhesion, cell infiltration or cytoskeleton organisation, suggesting lower immune cell adhesion to endothelial cells. This was corroborated by in vitro experiments showing that MOF exposure of monocytes attenuates their adhesion to TNF-M-NM-1-stimulated endothelial cells. Nuclear factor-kappa B (NF-M-NM-:B) reporter gene assays confirmed that MOF decrease the activity of NF-M-NM-:B. Strong inter-individual variability in the leukocytesM-bM-^@M-^Y DNA methylation was observed. As a consequence, on group level, changes due to MOF supplementation could not be found. However, in individuals, significant changes in DNA methylation of genes involved in leukocyte rolling, adhesion and cytoskeleton remodelling were seen. Conclusion: Our study revealed that regular consumption of MOF modulates the expression of genes in immune cells which, however, cannot be correlated to alterations in the DNA methylome. Remarkably, at the individual level, genes related to leukocyte adhesion pathways present complex variation in DNA methylation. As such, the individual transcriptional and epigenetic modulation of genes involved in early manifestation of cardiovascular diseases constitutes important subcellular mechanisms by which MOF promote vascular health in humans. DNA methylation levels of blood samples from 10 subjects were assessed using HumanMethylation450 BeadChips (Illumina), both before and after a diet intervention with MOF.

Project description:Background: In a recent intervention study, the daily supplementation with 200mg monomeric and oligomeric flavanols (MOF) from grape seeds for 8 weeks revealed a vascular health benefit in male smokers. The objective of the present study was to determine the impact of MOF consumption on the gene expression profile of leukocytes and to assess changes in DNA methylation. Methodology/Principal Findings: Gene expression profiles were determined using whole genome microarrays (Agilent) and DNA methylation was assessed using HumanMethylation450 BeadChips (Illumina). MOF significantly modulated the expression of 869 genes. The majority of the affected genes are involved in chemotaxis, cell adhesion, cell infiltration or cytoskeleton organisation, suggesting lower immune cell adhesion to endothelial cells. This was corroborated by in vitro experiments showing that MOF exposure of monocytes attenuates their adhesion to TNFM-NM-1-stimulated endothelial cells. Nuclear factor-kappa B reporter gene assays confirmed that MOF decrease the activity of NF-M-NM-:B. Strong inter-individual variability in the leukocytes DNA methylation was observed. As a consequence, on group level, changes due to MOF supplementation could not be found. However, in individuals, significant changes in DNA methylation of genes involved in leukocyte rolling, adhesion and cytoskeleton remodelling were seen. At the group level, the variation in DNA methylation related to life style and clinical parameters appeared to overrule the magnitude of effects of supplementation with MOF. Conclusion: Our study revealed that regular consumption of MOF modulates the expression of genes in immune cells which, however, cannot be correlated to alterations in the DNA methylome. Remarkably, at the individual level, genes related to leukocyte adhesion pathways present complex variation in DNA methylation. As such, the individual transcriptional and epigenetic modulation of genes involved in early manifestation of cardiovascular diseases constitutes important subcellular mechanisms by which MOF promote vascular health in humans. Two-colors experiment, 7 volunteers : blood samples of 7 men, before and after an intervention of 8 weeks with daily intake of MOF (14 samples).

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Epicatechin metabolites exert epigenetic regulation in endothelial cells by modulating DNA methylation profile

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