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A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue.

ABSTRACT: Epigenetic mechanisms are implicated in gene regulation and the development of different diseases. The epigenome differs between cell types and has until now only been characterized for a few human tissues. Environmental factors potentially alter the epigenome. Here we describe the genome-wide pattern of DNA methylation in human adipose tissue from 23 healthy men, with a previous low level of physical activity, before and after a six months exercise intervention. We also investigate the differences in adipose tissue DNA methylation between 31 individuals with or without a family history of type 2 diabetes. DNA methylation was analyzed using Infinium HumanMethylation450 BeadChip, an array containing 485,577 probes covering 99% RefSeq genes. Global DNA methylation changed and 17,975 individual CpG sites in 7,663 unique genes showed altered levels of DNA methylation after the exercise intervention (q<0.05). Differential mRNA expression was present in 1/3 of gene regions with altered DNA methylation, including RALBP1, HDAC4 and NCOR2 (q<0.05). Using a luciferase assay, we could show that increased DNA methylation in vitro of the RALBP1 promoter suppressed the transcriptional activity (p?=?0.03). Moreover, 18 obesity and 21 type 2 diabetes candidate genes had CpG sites with differences in adipose tissue DNA methylation in response to exercise (q<0.05), including TCF7L2 (6 CpG sites) and KCNQ1 (10 CpG sites). A simultaneous change in mRNA expression was seen for 6 of those genes. To understand if genes that exhibit differential DNA methylation and mRNA expression in human adipose tissue in vivo affect adipocyte metabolism, we silenced Hdac4 and Ncor2 respectively in 3T3-L1 adipocytes, which resulted in increased lipogenesis both in the basal and insulin stimulated state. In conclusion, exercise induces genome-wide changes in DNA methylation in human adipose tissue, potentially affecting adipocyte metabolism.

SUBMITTER: Ronn T

PROVIDER: S-EPMC3694844 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue.

Rönn Tina T Volkov Petr P Davegårdh Cajsa C Dayeh Tasnim T Hall Elin E Olsson Anders H AH Nilsson Emma E Tornberg Asa A Dekker Nitert Marloes M Eriksson Karl-Fredrik KF Jones Helena A HA Groop Leif L Ling Charlotte C

PLoS genetics 20130627 6

Epigenetic mechanisms are implicated in gene regulation and the development of different diseases. The epigenome differs between cell types and has until now only been characterized for a few human tissues. Environmental factors potentially alter the epigenome. Here we describe the genome-wide pattern of DNA methylation in human adipose tissue from 23 healthy men, with a previous low level of physical activity, before and after a six months exercise intervention. We also investigate the differen ...[more]

PMID: 23825961

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Project description:BackgroundStudies have shown that the effects of maternal nutrition exposure during gestation influence metabolic risk in early life through an epigenetic mechanism. Low glycaemic index (GI) diets benefit both maternal and neonatal gestational outcomes. We hypothesize that maternal dietary GI or glycaemic load (GL) changes during pregnancy impact placental DNA methylation, especially in insulin resistance-related genes.MethodsFrom a clinical trial of overweight pregnant women, 12 subjects who successfully reduced their GI and another 12 whose GI increased despite the intervention were selected. A genome-wide differential methylation analysis of placental tissue DNA was conducted, followed by bioinformatic annotation and validation analysis. The distribution of genome-wide differentially methylated regions (DMRs) and CpG sites was described. Six CpG sites in regulatory regions of four insulin-related genes (PLIN1, CPT1B, SSTR4, and CIDEA) were selectively validated by pyrosequencing. Pairwise Spearman correlation analysis was performed to test methylation-phenotype association in an additional 153 subjects from the same trial. Correlation between methylation of significant sites and placental mRNA expression of SSTR4 was also analysed.ResultsDietary GI decreased by 24.3 (26.2-20.1) in the group who responded appropriately to the intervention and increased by 19.6 (15.2-29.1) in the comparison group. Epigenome-wide analysis identified 108 DMRs and 365 CpG sites with P < 0.05 adjusted by false discovery rate, distributed over all chromosomes. The methylation level of cg05009389 in the 3' UTR of PLIN1 was negatively correlated with maternal weight gain (ρ = - 0.21, P = 0.027) and increase in insulin levels (ρ = - 0.24, P = 0.015) during gestation. Methylation levels of cg17586860 and cg18197392 in the 5' UTR region of SSTR4 were negatively correlated with changes in dietary carbohydrate intake (ρ = - 0.24, Ps ≤ 0.006) and GL across gestation (ρ = - 0.23, Ps ≤ .008). This correlation survived the adjustment for maternal factors such as dietary GI, body mass index, and gestational diabetes. Up to 89% of cg18197392 methylation was explained by GL change. Cg14631053 methylation correlated positively with mRNA expression of SSTR4 in the placenta (ρ = 0.20, P = 0.037).ConclusionsWe provide the first evidence that maternal dietary GI changes during gestation may impact placental DNA methylation of insulin regulation genes. This supports the hypothesis that placental methylation may be the epigenetic mechanism through which maternal diet influences the metabolic health of offspring.

Dataset Information

A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue.

Publications

A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue.

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