Epigenome-wide association in adipose tissue from the METSIM cohort

Abstract

Most epigenome-wide association studies to date have been conducted in blood. However, metabolic syndrome is mediated by a dysregulation of adiposity and therefore it is critical to study adipose tissue in order to understand the effects of this syndrome on epigenomes. To determine if natural variation in DNA methylation was associated with metabolic syndrome traits, we profiled global methylation levels in subcutaneous abdominal adipose tissue. We measured association between 32 clinical traits related to diabetes and obesity in 201 people from the Metabolic Syndrome in Men cohort. We performed epigenome-wide association studies between DNA methylation levels and traits, and identified associations for 13 clinical traits in 21 loci. We prioritized candidate genes in these loci using expression quantitative trait loci, and identified 18 high confidence candidate genes, including known and novel genes associated with diabetes and obesity traits. Using methylation deconvolution, we examined which cell types may be mediating the associations, and concluded that most of the loci we identified were specific to adipocytes. We determined whether the abundance of cell types varies with metabolic traits, and found that macrophages increased in abundance with the severity of metabolic syndrome traits. Finally, we developed a DNA methylation-based biomarker to assess type 2 diabetes risk in adipose tissue. In conclusion, our results demonstrate that profiling DNA methylation in adipose tissue is a powerful tool for understanding the molecular effects of metabolic syndrome on adipose tissue, and can be used in conjunction with traditional genetic analyses to further characterize this disorder.

Adipose Tissue Epigenetic Profile in Obesity-Related Dysglycemia - A Systematic Review

“…Amongst the 23 papers included in this systematic review, 19 papers reported studies on DNA methylation, 2 papers presented data on histone modifications and 2 papers conducted studies on lncRNAs. Of the 19 papers that reported data on DNA methylation in AT from individuals with MUHO, 8 papers performed targeted epigenome studies (52-59) and 11 papers reported genome-wide studies (60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70). The main findings on the targeted DNA methylation studies are summarized in Table 1.…”

“…The majority of the DNA methylation epigenome-wide studies relied on an array-based methodology, while 2 studies used the Reduced Representation Bisulfite Sequencing (RRBS) method for identifying DMRs (60,66). Most studies included adjustments for age, sex and BMI in the analysis.…”

Genome-wide DNA Methylation Profiling of Blood from Monozygotic Twins Discordant for Myocardial Infarction

“…Differential methylation analysis. DNA from the twins was used to prepare RRBS libraries as described previously with minor modifications (14). The libraries were sequenced using an Illumina HiSeq4000 yielding more than 20 million reads for each twin.…”

“…DNA methylation assay. Genomic DNA was isolated by standard phenol-chloroform extraction method and used as input to prepare RRBS libraries as described previously (14) with minor modifications. For each sample, 50-100 ng of purified genomic DNA was digested with 20 U of MspI (NEB, USA) at 37˚C o/n in the presence of RNase Cocktail Mix (Ambion, USA).…”

Protocol for a prospective, observational, deep phenotyping study on adipose epigenetic and lipidomic determinants of metabolic homoeostasis in South Asian Indians: the Indian Diabetes and Metabolic Health (InDiMeT) study

“…The InDiMeT study proposes to achieve this by conducting detailed phenotyping and phenome measurements in a prospective manner in a high-risk population setting. Though animal studies have underlined the epigenetic changes in the adipose associated, few have investigated adipose epigenetics in humans and none in the context of adipose DNL dysregulation and T2DM [10][11][12] which will help to identify epigenomic dysregulation of adipose DNL in T2DM AT. Although DNA methylation signatures are specific to tissue and cell types, only ~38% of the DNA methylation probes have been reported to be differentially methylated in blood in a tissue-specific fashion, implying likelihood of the rest ~62% probes being conservatively methylated between blood and other tissues.…”