Abstract
Age, gender, diet, gene and lifestyle have been reported to affect metabolic status and disease susceptibility through epigenetic pathway. But it remains indistinct that which factors account for certain epigenetic modifications. Our aim was to identify the influencing factors on inter-individual DNA methylation variations of carbohydrate response element binding protein (ChREBP) and global genome in peripheral blood leucocytes (PBLs). ChREBP DNA methylation was determined by bisulfite sequencing, and genomic 5mdC contents were quantified by capillary hydrophilic-interaction liquid chromatography/ in-source fragmentation/ tandem mass spectrometry system in about 300 healthy individuals. Eleven single nucleotide polymorphisms (SNPs) spanning ChREBP and DNA methyltransferase 1 (DNMT1) were genotyped by high resolution melting or PCR-restriction fragment length polymorphism. DNMT1 mRNA expression was analyzed by quantitative PCR. We found ChREBP DNA methylation levels were statistically associated with age (Beta (B) = 0.028, p = 0.006) and serum total cholesterol concentrations (TC) (B = 0.815, p = 0.010), independent of sex, concentrations of triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol (LDL-C), fasting blood glucose and systolic blood pressure, diastolic blood pressure, PBLs counts and classifications. The DNMT1 haplotypes were related to ChREBP (odds ratio (OR) = 0.668, p = 0.029) and global (OR = 0.450, p = 0.015) DNA methylation as well as LDL-C, but not DNMT1 expression. However, only the relation to LDL-C was robust to correction for multiple testing (ORFDR = 1.593, pFDR = 0.013). These results indicated that the age and TC were independent influential factors of ChREBP methylation and DNMT1 variants could probably influence LDL-C to further modify ChREBP DNA methylation. Certainly, sequential comprehensive analysis of the interactions between genetic variants and blood lipid levels on ChREBP and global DNA methylation was required.
Highlights
DNA methylation is a main epigenetic mechanism that affects gene transcription [1], tissue differentiation [2] and chromatin remodeling [3]
We found that carbohydrate response element binding protein (ChREBP) DNA methylation was correlated with age, total cholesterol concentrations (TC), total glyceride (TG), low density lipoprotein cholesterol (LDL-C), but was not related to sex, high density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG), systolic blood pressure (SBP), diastolic blood pressure (DBP), peripheral blood leucocytes (PBLs) counts and classifications
Since DNA methyltransferase 1 (DNMT1) plays a major role in the maintenance of methylation patterns, 5 tag single nucleotide polymorphisms (SNPs) within DNMT1 were genotyped to estimate the trans-effect of genetic variants on ChREBP DNA methylation
Summary
DNA methylation is a main epigenetic mechanism that affects gene transcription [1], tissue differentiation [2] and chromatin remodeling [3]. Investigations have implicated inter-individual DNA methylation variations with age, gender, diet, lifestyle, and genetic variants [14,15,16,17,18] especially single nucleotide polymorphisms (SNPs) in the DNA methyltransferases 1 (DNMT1), which could bind methyl groups to hemi-methylated DNA [19]. These SNPs could affect DNMT1 protein folding, catalytic activity and heterochromatin binding ability, leading to the changes of global and loci-specific DNA methylation [20,21,22]. Substantially less is known about the exact interactions among epigenetic variations, genetic variants and environmental factors
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