Genome-wide blood DNA methylation alterations at regulatory elements and heterochromatic regions in monozygotic twins discordant for obesity and liver fatReportar como inadecuado

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Clinical Epigenetics

, 7:39

First Online: 02 April 2015Received: 17 October 2014Accepted: 11 March 2015


BackgroundThe current epidemic of obesity and associated diseases calls for swift actions to better understand the mechanisms by which genetics and environmental factors affect metabolic health in humans. Monozygotic MZ twin pairs showing discordance for obesity suggest that epigenetic influences represent one such mechanism. We studied genome-wide leukocyte DNA methylation variation in 30 clinically healthy young adult MZ twin pairs discordant for body mass index BMI; average within-pair BMI difference: 5.4 ± 2.0 kg-m.

ResultsThere were no differentially methylated cytosine-guanine CpG sites between the co-twins discordant for BMI. However, stratification of the twin pairs based on the level of liver fat accumulation revealed two epigenetically highly different groups. Significant DNA methylation differences n = 1,236 CpG sites CpGs between the co-twins were only observed if the heavier co-twins had excessive liver fat n = 13 twin pairs. This unhealthy pattern of obesity was coupled with insulin resistance and low-grade inflammation. The differentially methylated CpGs included 23 genes known to be associated with obesity, liver fat, type 2 diabetes mellitus T2DM and metabolic syndrome, and potential novel metabolic genes. Differentially methylated CpG sites were overrepresented at promoters, insulators, and heterochromatic and repressed regions. Based on predictions by overlapping histone marks, repressed and weakly transcribed sites were significantly more often hypomethylated, whereas sites with strong enhancers and active promoters were hypermethylated. Further, significant clustering of differentially methylated genes in vitamin, amino acid, fatty acid, sulfur, and renin-angiotensin metabolism pathways was observed.

ConclusionsThe methylome in leukocytes is altered in obesity associated with metabolic disturbances, and our findings indicate several novel candidate genes and pathways in obesity and obesity-related complications.

KeywordsDNA methylation Epigenetics Monozygotic twins Obesity Liver fat AbbreviationsBMIbody mass index

BMIQbeta-mixture quantile normalization

CGIsCpG islands

CpGsCpG sites

EDEuclidean distance

eLF groupelevated liver fat group

EWASepigenome-wide association studies

FDRfalse discovery rate

GSAgene set analysis

GWASgenome-wide association studies

MetSmetabolic syndrome


nLF groupnormal liver fat group

T2DMtype 2 diabetes mellitus

Kirsi H Pietiläinen and Jaakko Kaprio contributed equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1186-s13148-015-0073-5 contains supplementary material, which is available to authorized users.

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