Abstract
BackgroundMonozygotic twins discordant for type 2 diabetes constitute an ideal model to study environmental contributions to type 2 diabetic traits. We aimed to examine whether global DNA methylation differences exist in major glucose metabolic tissues from these twins.Methodology/Principal FindingsSkeletal muscle (n = 11 pairs) and subcutaneous adipose tissue (n = 5 pairs) biopsies were collected from 53–80 year-old monozygotic twin pairs discordant for type 2 diabetes. DNA methylation was measured by microarrays at 26,850 cytosine-guanine dinucleotide (CpG) sites in the promoters of 14,279 genes. Bisulfite sequencing was applied to validate array data and to quantify methylation of intergenic repetitive DNA sequences. The overall intra-pair variation in DNA methylation was large in repetitive (LINE1, D4Z4 and NBL2) regions compared to gene promoters (standard deviation of intra-pair differences: 10% points vs. 4% points, P<0.001). Increased variation of LINE1 sequence methylation was associated with more phenotypic dissimilarity measured as body mass index (r = 0.77, P = 0.007) and 2-hour plasma glucose (r = 0.66, P = 0.03) whereas the variation in promoter methylation did not associate with phenotypic differences. Validated methylation changes were identified in the promoters of known type 2 diabetes-related genes, including PPARGC1A in muscle (13.9±6.2% vs. 9.0±4.5%, P = 0.03) and HNF4A in adipose tissue (75.2±3.8% vs. 70.5±3.7%, P<0.001) which had increased methylation in type 2 diabetic individuals. A hypothesis-free genome-wide exploration of differential methylation without correction for multiple testing identified 789 and 1,458 CpG sites in skeletal muscle and adipose tissue, respectively. These methylation changes only reached some percentage points, and few sites passed correction for multiple testing.Conclusions/SignificanceOur study suggests that likely acquired DNA methylation changes in skeletal muscle or adipose tissue gene promoters are quantitatively small between type 2 diabetic and non-diabetic twins. The importance of methylation changes in candidate genes such as PPARGC1A and HNF4A should be examined further by replication in larger samples.
Highlights
Type 2 diabetes (T2D) is a heterogeneous and complex disease resulting from a combination of impaired pancreatic insulin secretion and insulin resistance in tissues such as skeletal muscle, adipose tissue, and liver
Conclusions/Significance: Our study suggests that likely acquired DNA methylation changes in skeletal muscle or adipose tissue gene promoters are quantitatively small between type 2 diabetic and non-diabetic twins
Twin pair was a significant predictor of overall methylation pattern in both skeletal muscle (P,0.001) and subcutaneous adipose tissue (SAT) (P,0.001), whereas overall methylation did not differ according to diabetes status (P.0.1)
Summary
Type 2 diabetes (T2D) is a heterogeneous and complex disease resulting from a combination of impaired pancreatic insulin secretion and insulin resistance in tissues such as skeletal muscle, adipose tissue, and liver. Phenotypic discordance in monozygotic twins is traditionally attributed to environmental factors distinct for each individual. Paired analyses of monozygotic twins discordant for a disease phenotype provide an excellent tool for examination of the environmental contribution to the disease in question. Epigenetics is traditionally referred to as heritable changes in gene expression which are not due to any alteration in DNA sequence. Epigenetics is altered by environmental factors and represents a potential mechanism through which the environment may cause phenotypic variation [12]. Two major classes of epigenetic modifications of the chromatin exist: methylation of cytosine, mostly at cytosineguanine dinucleotides (CpG)s, and histone modifications, notably acetylations and methylations. We aimed to examine whether global DNA methylation differences exist in major glucose metabolic tissues from these twins
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