Altered DNA-methylation has a well-documented mechanistic role in modulating gene expression. However, its contribution in modulating adipose tissue gene expression and insulin sensitivity (SI) in African Americans (AAs) is unknown. To understand the role of differential DNA methylation in determining SI we selected 12 insulin resistant (IR) and 12 insulin sensitive (IS) individuals from a cohort 253 nondiabetic AAs. IR and IS individuals were selected from the extremes of the distribution of SI (1.49±0.69 vs. 8.23±4.48), and expression levels of insulin resistance-associated transcripts in AAGMEx cohort. Reduced representation bisulfite sequencing (RRBS; >30M read) was used to quantify epigenome-wide DNA methylation levels in adipose DNA samples. To determine differentially methylated sites (DMS) linear regressions adjusting for age and sex were used to test for DMS at 774,095 CpG sites (≥ 10X coverage) passing quality control. We identified 8387 hypermethylated and 2532 hypomethylated autosomal DMS in IR individuals (mean methylation difference ≥5% and genomic control corrected-p ≤0.05). Among these DMS, 6414 were annotated to exon, intron or promoter regions of 3923 genes. Highest number of DMS (22, including 20 hypermethylated (5.5-30.2%) DMS) were annotated to PRDM16, a transcription co-factor critical for the development of brown adipocytes. We merged the DMS 3923 genes with 663 differentially expressed transcripts (GC-p≤0.05 and fold change ≥1.2) and identified 123 IR-associated genes with DMS. Genes containing hypermethylated CpG sites and downregulated expression in IR were enriched for long-chain fatty-acyl-CoA biosynthetic process (B-H p=0.0013, includes ELOVL6, ACSF2, ACOT2, FASN, and TECR), and mitochondrion (B-H p=0.0016, 14 genes).

In summary, differential DNA-methylation of a subset of genes in adipose tissue modulate expression of transcripts in key biological pathways and may determine insulin sensitivity.


N.K. Sharma: None. M.E. Comeau: None. C.D. Langefeld: None. S.K. Das: None.


American Diabetes Association (1-18-ICTS-113 to S.K.D.); National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases

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