Genome-wide DNA methylation analysis reveals loci that distinguish different types of adipose tissue in obese individuals

Abstract

BackgroundEpigenetic mechanisms provide an interface between environmental factors and the genome and are known to play a role in complex diseases such as obesity. These mechanisms, including DNA methylation, influence the regulation of development, differentiation and the establishment of cellular identity. Here we employ two approaches to identify differential methylation between two white adipose tissue depots in obese individuals before and after gastric bypass and significant weight loss. We analyse genome-wide DNA methylation data using (a) traditional paired t tests to identify significantly differentially methylated loci (Bonferroni-adjusted P ≤ 1 × 10−7) and (b) novel combinatorial algorithms to identify loci that differentiate between tissue types.ResultsSignificant differential methylation was observed for 3239 and 7722 CpG sites, including 784 and 1129 extended regions, between adipose tissue types before and after significant weight loss, respectively. The vast majority of these extended differentially methylated regions (702) were consistent across both time points and enriched for genes with a role in transcriptional regulation and/or development (e.g. homeobox genes). Other differentially methylated loci were only observed at one time point and thus potentially highlight genes important to adipose tissue dysfunction observed in obesity. Strong correlations (r > 0.75, P ≤ 0.001) were observed between changes in DNA methylation (subcutaneous adipose vs omentum) and changes in clinical trait, in particular for CpG sites within PITX2 and fasting glucose and four CpG sites within ISL2 and HDL. A single CpG site (cg00838040, ATP2C2) gave strong tissue separation, with validation in independent subcutaneous (n = 681) and omental (n = 33) adipose samples.ConclusionsThis is the first study to report a genome-wide DNA methylome comparison of subcutaneous abdominal and omental adipose before and after weight loss. The combinatorial approach we utilised is a powerful tool for the identification of methylation loci that strongly differentiate between these tissues. This study provides a solid basis for future research focused on the development of adipose tissue and its potential dysfunction in obesity, as well as the role DNA methylation plays in these processes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-017-0344-4) contains supplementary material, which is available to authorized users.

Genetics and epigenetics in obesity

“…Numerous intervention studies examining the effects of physical activity or weight loss due to bariatric surgery on DNA methylation clearly corroborates the vast evidence for correlations of clinical variables with epigenetic signatures. An early study [119] Accordingly, a similar study revealed specific differentially methylated loci between SAT and OVAT before and after weight loss surgery [128]. Others described changes in DNA methylation levels after RYGB related to improvements in fatty acid metabolism [129] and systolic blood pressure [130].…”

MicroRNA Profiling in Adipose Before and After Weight Loss Highlights the Role of miR‐223‐3p and the NLRP3 Inflammasome

“…Therefore, we applied a combinatorial approach to identify miRNA signatures that discriminated the time points. We have previously applied this methodology to both mRNA expression and DNA methylation data . In subcutaneous adipose, 6/13 miRNAs identified as significantly differentially expressed (miR‐1246, miR‐22‐3p, miR‐421, and the miRNA cluster miR‐23a‐5p, miR‐24‐2‐5p, and miR‐27a‐5p) passed filtering and had positive merit scores (estimates the relative ability of a miRNA to distinguish among sample classes) and a strong ability to separate between time points through the distribution of pairwise calculated intersample scores (Figure ).…”

ISL2 is an epigenetically silenced tumor suppressor and regulator of metabolism in pancreatic cancer

“…ISL2 (also called Islet 2) encodes a TF harboring 2 LIM protein-interacting domains and a homeobox DNA binding domain (LIM/HD), which is implicated in neuronal specification 27,28 and adipose tissue heterogeneity 29 . While ISL2 has not previously been examined in cancer, 10 of 12 related LIM/HD TFs are thought to have cancer-relevant functions 30 .…”