Maternal folate depletion during early development and high fat feeding from weaning elicit similar changes in gene expression, but not in DNA methylation, in adult offspring

Objective: One of the first clinically detectable changes in the vasculature during atherogenesis is the accumulation of cholesterol within the vessel wall. Hypercholesterolemia is characterized by dysfunctional endothelial-dependent vessel relaxation and impaired NOS3 function. Since DNA methylation at gene promoter regions strongly suppresses gene expression, we postulated that high-fat/high-cholesterol diet suppresses endothelial NOS3 through promoter DNA methylation. Methods: Domestic male pigs were fed control diet (CD) or isocaloric high fat and high cholesterol diet (HC; 12% fat and 1.5% cholesterol) for 2, 4, 8 or 12 weeks prior to tissue collection. Furthermore, to determine the effects of risk factor withdrawal, an additional group of swine received HC for 12 weeks and then CD for 8 weeks; a control group received HC continuously for 20 weeks. Endothelial cells were harvested from common carotid aorta. In parallel in vitro studies, cultured human aortic endothelial cells (HAEC) were treated with human LDL, GW3956 (LXR agonist) and RG108 (DNA methyltransferase [DNMT] inhibitor). In cells from both sources, DNA methylation at the NOS3 promoter was measured using methylation specific pyro sequencing, and endothelial gene expression was measured using RT PCR. Results: HC diet increased plasma cholesterol level from 75 mg/dl on CD to a plateau of about 540 mg/dl within 2 weeks. Endothelial NOS3 expression was significantly reduced (71±9 % of CD) after 4 weeks of HC, a level sustained at subsequent time points. Withdrawal of HC for 8 weeks did not recover NOS3 expression. After 12-week HC, the NOS3 promoter was hypermethylated. Withdrawal of HC did not reverse NOS3 promoter methylation. In vitro treatment of HAEC with human LDL (200 mg/dl total cholesterol) or GW3956 (5μM) suppressed NOS3 mRNA to 50% and 30% respectively, suggesting that LXR/RXR is involved in suppression of NOS3. Nitric oxide production was consistently suppressed by GW3959. Both could be reversed through inhibition of DNMTs by RG108. Conclusions: DNA methylation and LXR/RXR pathway can mediate the HC-suppression of endothelial NOS3. The study identifies novel pharmaceutical targets in treating endothelial dysfunction. Crosstalk between these pathways is under investigation.

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Folate depletion during pregnancy and lactation reduces genomic DNA methylation in murine adult offspring

Genes & Nutrition ◽

10.1007/s12263-010-0199-1 ◽

2010 ◽

Vol 6 (2) ◽

pp. 189-196 ◽

Cited By ~ 56

Author(s):

Jill A. McKay ◽

Kevin J. Waltham ◽

Elizabeth A. Williams ◽

John C. Mathers

Keyword(s):

Dna Methylation ◽

Genomic Dna ◽

Adult Offspring ◽

Pregnancy And Lactation ◽

Folate Depletion

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Maternal Nutrition Induces Pervasive Gene Expression Changes but No Detectable DNA Methylation Differences in the Liver of Adult Offspring

PLoS ONE ◽

10.1371/journal.pone.0090335 ◽

2014 ◽

Vol 9 (3) ◽

pp. e90335 ◽

Cited By ~ 30

Author(s):

Matthew V. Cannon ◽

David A. Buchner ◽

James Hester ◽

Hadley Miller ◽

Ephraim Sehayek ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Maternal Nutrition ◽

Adult Offspring

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Resveratrol Supplementation Attenuates Cognitive and Molecular Alterations Under Maternal High-Fat Diet Intake: Multigenerational Epigenetic Inheritance.

10.20944/preprints202012.0115.v1 ◽

2020 ◽

Author(s):

Vanesa Izquierdo ◽

Verónica Palomera-Ávalos ◽

Mercè Pallàs ◽

Christian Griñán-Ferré

Keyword(s):

Gene Expression ◽

Cognitive Decline ◽

High Fat Diet ◽

Epigenetic Inheritance ◽

Adult Offspring ◽

High Fat ◽

Molecular Alterations ◽

Protein Levels ◽

Age Related ◽

Inflammatory Profile

Environmental factors as maternal high-fat diet (HFD) intake can increase the risk of age-related cognitive decline in adult offspring. The epigenetic mechanisms are a possible link between diet effect and neurodegeneration across generations. Here, we found a significant decrease in triglyceride levels in a high-fat diet with resveratrol HFD+RV group and the offspring. Firstly, we obtained better cognitive performance in HFD+RV groups and their offspring. Molecularly, a significant increase in 5-mC levels, as well as increased gene expression of Dnmt1 and Dnmt3a in HFD+RV F1 group, were found. Furthermore, a significantly increased of m6A levels in HFD+RV F1 were found, and there were changes in gene expression of its enzymes (Mettl3 and Fto). Moreover, we found a decrease in gene expression levels of pro-inflammatory markers such as Il1-β, Il-6, Tnf-α, Cxcl-10, Mcp-1 and Tgf-β1 in HFD+RV and HFD+RV F1 groups. Moreover, there was increased gene expression of neurotrophins such as Ngf and Nt3 and its receptors TrkA and TrkB. Likewise, an increase in protein levels of BDNF and p-Akt in HFD+RV F1 was found. These results suggest that maternal RV supplementation under HFD intake prevents cognitive decline in SAMP8 adult offspring, promoting a reduction in triglycerides and leptin plasma levels, changes in the pro-inflammatory profile, restoring the epigenetic landscape as well as synaptic plasticity.

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Maternal and Post-weaning High-Fat Diets Produce Distinct DNA Methylation Patterns in Hepatic Metabolic Pathways within Specific Genomic Contexts

International Journal of Molecular Sciences ◽

10.3390/ijms20133229 ◽

2019 ◽

Vol 20 (13) ◽

pp. 3229 ◽

Cited By ~ 4

Author(s):

Moody ◽

Wang ◽

Jung ◽

Chen ◽

Pan

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Metabolic Pathways ◽

Expression Patterns ◽

Sprague Dawley ◽

High Fat ◽

Differentially Methylated Genes ◽

High Fat Diets ◽

Diet Intake ◽

Fat Diets

Calorie-dense high-fat diets (HF) are associated with detrimental health outcomes, including obesity, cardiovascular disease, and diabetes. Both pre- and post-natal HF diets have been hypothesized to negatively impact long-term metabolic health via epigenetic mechanisms. To understand how the timing of HF diet intake impacts DNA methylation and metabolism, male Sprague–Dawley rats were exposed to either maternal HF (MHF) or post-weaning HF diet (PHF). At post-natal week 12, PHF rats had similar body weights but greater hepatic lipid accumulation compared to the MHF rats. Genome-wide DNA methylation was evaluated, and analysis revealed 1744 differentially methylation regions (DMRs) between the groups with the majority of the DMR located outside of gene-coding regions. Within differentially methylated genes (DMGs), intragenic DNA methylation closer to the transcription start site was associated with lower gene expression, whereas DNA methylation further downstream was positively correlated with gene expression. The insulin and phosphatidylinositol (PI) signaling pathways were enriched with 25 DMRs that were associated with 20 DMGs, including PI3 kinase (Pi3k), pyruvate kinase (Pklr), and phosphodiesterase 3 (Pde3). Together, these results suggest that the timing of HF diet intake determines DNA methylation and gene expression patterns in hepatic metabolic pathways that target specific genomic contexts.

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