Abstract
BackgroundEnvironmental factors can influence obesity by epigenetic mechanisms. Adipose tissue plays a key role in obesity-related metabolic dysfunction, and gastric bypass provides a model to investigate obesity and weight loss in humans.ResultsHere, we investigate DNA methylation in adipose tissue from obese women before and after gastric bypass and significant weight loss. In total, 485,577 CpG sites were profiled in matched, before and after weight loss, subcutaneous and omental adipose tissue. A paired analysis revealed significant differential methylation in omental and subcutaneous adipose tissue. A greater proportion of CpGs are hypermethylated before weight loss and increased methylation is observed in the 3′ untranslated region and gene bodies relative to promoter regions. Differential methylation is found within genes associated with obesity, epigenetic regulation and development, such as CETP, FOXP2, HDAC4, DNMT3B, KCNQ1 and HOX clusters. We identify robust correlations between changes in methylation and clinical trait, including associations between fasting glucose and HDAC4, SLC37A3 and DENND1C in subcutaneous adipose. Genes investigated with differential promoter methylation all show significantly different levels of mRNA before and after gastric bypass.ConclusionsThis is the first study reporting global DNA methylation profiling of adipose tissue before and after gastric bypass and associated weight loss. It provides a strong basis for future work and offers additional evidence for the role of DNA methylation of adipose tissue in obesity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0569-x) contains supplementary material, which is available to authorized users.
Highlights
Environmental factors can influence obesity by epigenetic mechanisms
We investigated global DNA methylation (450,315 Cytosine guanine dinucleotide (CpG) sites passing quality filtering) and plotted this at the level of genomic gene annotation (Figure 1)
In order to investigate if the global pattern of methylation across gene regions was similar in other tissues we investigated publically available data from 15 different tissues
Summary
Environmental factors can influence obesity by epigenetic mechanisms. Adipose tissue plays a key role in obesity-related metabolic dysfunction, and gastric bypass provides a model to investigate obesity and weight loss in humans. Different adipose tissue depots within the body have distinct structural and biochemical properties [7,8]. In humans, these depots can broadly be divided into two categories, subcutaneous and intra-abdominal. Metabolic risk is affected by both the distribution of body fat between different adipose tissue depots within an individual and the Causal genetic variants of obesity and type-2 diabetes have been identified through candidate gene, family-based linkage and large scale association analyses. Apart from the small number of rare monogenic disease variants application of genetics to clinical management has not occurred Reasons for this include the relatively small effect size of common genetic variants, the location of a large number of disease associated loci in intergenic regions of the genome, and the likelihood that additional causal variants are yet to be identified [15,16]
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