title: Sex differences in the genome-wide DNA methylation pattern and impact on gene expression, microRNA levels and insulin secretion in human pancreatic islets.
abstract: BACKGROUND
  Epigenetic 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.
  
  
  RESULTS
  Glucose-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.
  
  
  CONCLUSIONS
  Chromosome-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.
authors.forename: Elin
authors.initials: E
authors.lastname: Hall
authors.forename: Petr
authors.initials: P
authors.lastname: Volkov
authors.forename: Tasnim
authors.initials: T
authors.lastname: Dayeh
authors.forename: Jonathan Lou S
authors.initials: JL
authors.lastname: Esguerra
authors.forename: Sofia
authors.initials: S
authors.lastname: Salö
authors.forename: Lena
authors.initials: L
authors.lastname: Eliasson
authors.forename: Tina
authors.initials: T
authors.lastname: Rönn
authors.forename: Karl
authors.initials: K
authors.lastname: Bacos
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ling
mesh_terms: D000368:Aged; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D015894:Genome, Human; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D012727:Sex Characteristics
chemical_list: D007328:Insulin; C585583:MIRN532 microRNA, human; C577172:MIRN660 microRNA, human; D035683:MicroRNAs