Abstract
BackgroundEpigenetic factors regulate tissue-specific expression and X-chromosome inactivation. Previous studies have identified epigenetic differences between sexes in some human tissues. However, it is unclear whether epigenetic modifications contribute to sex-specific differences in insulin secretion and metabolism. Here, we investigate the impact of sex on the genome-wide DNA methylation pattern in human pancreatic islets from 53 males and 34 females, and relate the methylome to changes in expression and insulin secretion.ResultsGlucose-stimulated insulin secretion is higher in female versus male islets. Genome-wide DNA methylation data in human islets clusters based on sex. While the chromosome-wide DNA methylation level on the X-chromosome is higher in female versus male islets, the autosomes do not display a global methylation difference between sexes. Methylation of 8,140 individual X-chromosome sites and 470 autosomal sites shows sex-specific differences in human islets. These include sites in/near AR, DUSP9, HNF4A, BCL11A and CDKN2B. 61 X-chromosome genes and 18 autosomal genes display sex-specific differences in both DNA methylation and expression. These include NKAP, SPESP1 and APLN, which exhibited lower expression in females. Functional analyses demonstrate that methylation of NKAP and SPESP1 promoters in vitro suppresses their transcriptional activity. Silencing of Nkap or Apln in clonal beta-cells results in increased insulin secretion. Differential methylation between sexes is associated with altered levels of microRNAs miR-660 and miR-532 and related target genes.ConclusionsChromosome-wide and gene-specific sex differences in DNA methylation associate with altered expression and insulin secretion in human islets. Our data demonstrate that epigenetics contribute to sex-specific metabolic phenotypes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0522-z) contains supplementary material, which is available to authorized users.
Highlights
Epigenetic factors regulate tissue-specific expression and X-chromosome inactivation
Sex differences in the genome-wide DNA methylation pattern in human pancreatic islets We evaluated if there are epigenetic differences between sexes in human pancreatic islets
We found that CpG sites with a different level of DNA methylation on autosomal chromosomes were underrepresented within the 5′ untranslated region (UTR) and enriched in intergenic regions (Figure 3E)
Summary
Epigenetic factors regulate tissue-specific expression and X-chromosome inactivation. We investigate the impact of sex on the genome-wide DNA methylation pattern in human pancreatic islets from 53 males and 34 females, and relate the methylome to changes in expression and insulin secretion. Epigenetic factors such as DNA methylation are known to play important roles in tissue-specific gene expression, cell differentiation and parental imprinting. In cells found in saliva, females tend to have higher DNA methylation levels on both the X chromosome as well as the autosomes [9] Many of these studies have only analyzed a limited number of genes and gene regions, such as the promoter region, and have not performed genome-wide analyses of DNA methylation. Sex-specific differences in DNA methylation levels have, to our knowledge, not yet been studied in human pancreatic islets
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