The functional significance of vascular DNA hypermethylation in atherosclerosis: a historical perspective.

A decade ago, independent mechanistic and descriptive epigenomics data demonstrated for the first time that vascular DNA hypermethylation is a landmark of and causal factor in human and murine atherosclerosis. Since then, a flurry of converging evidence has assigned a prominent role to vascular DNA hypermethylation across the natural history of cardiovascular disease (CVD), from the exposure to risk factors, to the onset and progression of the atheroma. DNA hypermethylation is induced by and mediates the metabolic outcomes of high-fat diets and CVD risk-enhancing lipids in several models.

A Survey of Fatty Acid Content of the Male Reproductive System in Mice Supplemented With Arachidonic Acid.

Paternal exposure to high-fat diets or individual fatty acids (FAs) including arachidonic acid (AA) modifies progeny traits by poorly understood mechanisms. Specific male reproductive system FAs may be involved in paternal inheritance, as they can modify a range of cellular components, including the epigenome. Our objective was to determine FAs in compartments of the male reproductive system that potentially affect ejaculate composition-right and left testicular interstitial fluid (TIF), vesicular gland fluid (VGF), and epididymal adipose tissue (EAT)-in mice exposed to AA or vehicle daily for 10 days ( = 9-10/group).

Correction: Effects of paternal arachidonic acid supplementation on offspring behavior and hypothalamus inflammation markers in the mouse.

[This corrects the article DOI: 10.1371/journal.pone.

Effects of paternal arachidonic acid supplementation on offspring behavior and hypothalamus inflammation markers in the mouse.

Arachidonic acid (AA) is involved in inflammation and plays a role in growth and brain development in infants. We previously showed that exposure of mouse sires to AA for three consecutive generations induces a cumulative change in fatty acid (FA) involved in inflammation and an increase in body and liver weight in the offspring. Here, we tested the hypothesis that paternal AA exposure changes the progeny's behavioral response to a proinflammatory insult, and asked whether tissue-specific FA are associated with that response.

Associations of fertility parameters with fatty acids and DNA methylation in Mexican women undergoing in vitro fertilization.

Background: Fatty acids (FA) likely affect human fertility at multiple levels, as deviations from physiological FA profiles are obesogenic, and FA can modify DNA methylation (DNAm). Yet, the interplay of follicular fluid (FF) and serum FA with BMI and percentage body fat (PBF) in human fertility is not completely understood. Also, associations of DNAm with fertility are largely unexplored.

Dynamic epigenetic age mosaicism in the human atherosclerotic artery.

Accelerated epigenetic ageing, a promising marker of disease risk, has been detected in peripheral blood cells of atherosclerotic patients, but evidence in the vascular wall is lacking. Understanding the trends of epigenetic ageing in the atheroma may provide insights into mechanisms of atherogenesis or identify targets for molecular therapy. We surveyed DNA methylation age in two human artery samples: a set of donor-matched, paired atherosclerotic and healthy aortic portions, and a set of carotid artery atheromas.

Cumulative Metabolic and Epigenetic Effects of Paternal and/or Maternal Supplementation with Arachidonic Acid across Three Consecutive Generations in Mice.

Apart from the known associations between arachidonic acid (AA), weight gain, and neurological and immune function, AA exposure leads to alterations in global and gene-specific DNA methylation (DNAm) and fatty acid (FA) content in human cultured cells. However, it is unknown as to whether the latter effects occur in vivo and are maintained over extended periods of time and across generations. To address this issue, we asked whether AA supplementation for three consecutive generations (prior to coitus in sires or in utero in dams) affected offspring growth phenotypes, in addition to liver DNAm and FA profiles in mice.

Distinct Associations of BMI and Fatty Acids With DNA Methylation in Fasting and Postprandial States in Men.

We have previously shown that blood global DNA methylation (DNAm) differs between postprandial state (PS) and fasting state (FS) and is associated with BMI and polyunsaturated fatty acid (PUFA) (negatively and positively, respectively) in 12 metabolically healthy adult Mexican men (AMM cohort) equally distributed among conventional BMI classes. Here, we detailed those associations at CpG dinucleotide level by exploiting the Infinium methylation EPIC array (Illumina). We sought differentially methylated CpG (dmCpG) that were (1) associated with BMI (BMI-dmCpG) and/or fatty acids (FA) (FA-dmCpG) in FS or PS and (2) different across FS and PS within a BMI class.

Somatic Genetic Mosaicism in the Apolipoprotein E-null Mouse Aorta.

In addition to genetic and epigenetic inheritance, somatic variation may contribute to cardiovascular disease (CVD) risk. CVD-associated somatic mutations have been reported in human clonal hematopoiesis, but evidence in the atheroma is lacking. To probe for somatic variation in atherosclerosis, we sought single-nucleotide private variants (PVs) in whole-exome sequencing (WES) data of aorta, liver, and skeletal muscle of two C57BL/6J coisogenic male ApoE null/wild-type (WT) sibling pairs, and RNA-seq data of one of the two pairs.

Is Any Cardiovascular Disease-Specific DNA Methylation Biomarker Within Reach?

Purpose Of Review: A detailed understanding of the epigenome of cardiovascular disease (CVD) should broaden current insights into mechanisms of atherogenesis and help identify suitable biomarkers for disease risk and progression. This review addresses the question whether a consensus has been reached on identifying the main aberrant DNA methylation profile in CVD. Additionally, it presents advances and setbacks in the search for specific CVD biomarkers.

Associations between atherosclerosis and neurological diseases, beyond ischemia-induced cerebral damage.

Neurodegeneration is traditionally viewed as a consequence of peptide accumulation in the brain, stroke and/or cerebral ischemia. Nonetheless, a number of scattered observations suggest that neurological disease and atherosclerosis may be linked by more complex mechanisms. Understanding the intricate link between atherosclerosis and neurological conditions may have a significant impact on the quality of life of the growing ageing population and of high cardiovascular risk groups in general.

Liver X Receptor-Binding DNA Motif Associated With Atherosclerosis-Specific DNA Methylation Profiles of Elements and Neighboring CpG Islands.

Background: The signals that determine atherosclerosis-specific DNA methylation profiles are only partially known. We previously identified a 29-bp DNA motif (differential methylation motif [DMM]) proximal to CpG islands (CGIs) that undergo demethylation in advanced human atheromas. Those data hinted that the DMM docks modifiers of DNA methylation and transcription.

Array probe density and pathobiological relevant CpG calling bias in human disease and physiological DNA methylation profiling.

The HumanMethylation450 BeadChip array (450K; Infinium) is a widely used tool in epigenomics. A recognized concern in the 450K platform is the potential effect of the number of probes/gene (PG) on ranking differentially methylated (DM) CpGs (DM-CpGs) before testing for enrichment of gene ontology categories. We previously showed in a fatty acid (FA)-induced DNA methylation profiling study that when DM-CpGs are ranked by the number of called DM-CpGs-to-PG ratio, the 150 top-ranking gene list is enriched in pathways that overlap with the corresponding Affymetrix array-based expression data.

Connecting the Dots Between Fatty Acids, Mitochondrial Function, and DNA Methylation in Atherosclerosis.

Purpose Of Review: The quest for factors and mechanisms responsible for aberrant DNA methylation in human disease-including atherosclerosis-is a promising area of research. This review focuses on the role of fatty acids (FAs) as modulators of DNA methylation-in particular the role of mitochondrial beta-oxidation in FA-induced changes in DNA methylation during the progression of atherosclerosis.

Recent Findings: Recent publications have advanced the knowledge in all areas touched by this review: the causal role of lipids in shaping the DNA methylome, the associations between chronic degenerative disease and mitochondrial function, the lipid composition of the atheroma, and the relevance of DNA hypermethylation in atherosclerosis.

11 beta-hydroxysteroid dehydrogenase 2 promoter methylation is associated with placental protein expression in small for gestational age newborns.

Small for gestational age infants have greater risk of developing metabolic diseases in adult life. It has been suggested that low birth weight may result from glucocorticoid excess in utero, a key mechanism in fetal programming. The placental enzyme 11-beta hydroxysteroid dehydrogenase type 2 (11β-HSD2, HSD11B2 gene) acts as a barrier protecting the fetus from maternal corticosteroid deleterious effects.

Leptin and its Receptors in Human Placenta of Small, Adequate, and Large for Gestational Age Newborns.

Alterations in birth weight impact postnatal outcome and adult metabolic health. Therefore, fetal growth regulation is crucial for preventing chronic metabolic diseases. Leptin has been suggested to play an important role in placental and fetal growth, albeit its specific mechanisms of action have not been elucidated.

Inter-individual variation in DNA methylation is largely restricted to tissue-specific differentially methylated regions in maize.

Background: Variation in DNA methylation across distinct genetic populations, or in response to specific biotic or abiotic stimuli, has typically been studied in leaf DNA from pooled individuals using either reduced representation bisulfite sequencing, whole genome bisulfite sequencing (WGBS) or methylation sensitive amplified polymorphism (MSAP). The latter represents a useful alterative when sample size is large, or when analysing methylation changes in genomes that have yet to be sequenced. In this study we compared variation in methylation across ten individual leaf and endosperm samples from maize hybrid and inbred lines using MSAP.

Activity of Extracts from Submerged Cultured Mycelium of Winter Mushroom, Flammulina velutipes (Agaricomycetes), on the Immune System In Vitro.

Extracts from submerged cultured mycelium of two strains of Flammulina velutipes, a popular culinary mushroom, were obtained by ultrasound and tested in vitro to determine their activity in innate immunity (monocytes/ macrophages). In addition, polyclonal antibodies against the extracts were produced. Both extracts have similar glycoproteins that contain mannose and glucose but have different glycoproteins with galactoseamine units.

Associations between whole peripheral blood fatty acids and DNA methylation in humans.

Fatty acids (FA) modify DNA methylation in vitro, but limited information is available on whether corresponding associations exist in vivo and reflect any short-term effect of the diet. Associations between global DNA methylation and FAs were sought in blood from lactating infants (LI; n = 49) and adult males (AMM; n = 12) equally distributed across the three conventional BMI classes. AMM provided multiple samples at 2-hour intervals during 8 hours after either a single Western diet-representative meal (post-prandial samples) or no meal (fasting samples).

Arachidonic and oleic acid exert distinct effects on the DNA methylome.

Abnormal fatty acid metabolism and availability are landmarks of metabolic diseases, which in turn are associated with aberrant DNA methylation profiles. To understand the role of fatty acids in disease epigenetics, we sought DNA methylation profiles specifically induced by arachidonic (AA) or oleic acid (OA) in cultured cells and compared those with published profiles of normal and diseased tissues. THP-1 monocytes were stimulated with AA or OA and analyzed using Infinium HumanMethylation450 BeadChip (Illumina) and Human Exon 1.

The trans fatty acid elaidate affects the global DNA methylation profile of cultured cells and in vivo.

Background: The deleterious effects of dietary trans fatty acids (tFAs) on human health are well documented. Although significantly reduced or banned in various countries, tFAs may trigger long-term responses that would represent a valid human health concern, particularly if tFAs alter the epigenome.

Methods: Based on these considerations, we asked whether the tFA elaidic acid (EA; tC18:1) has any effects on global DNA methylation and the transcriptome in cultured human THP-1 monocytes, and whether the progeny of EA-supplemented dams during either pregnancy or lactation in mice (n = 20 per group) show any epigenetic change after exposure.