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Sex differences in the genome-wide DNA methylation pattern and impact on gene expression, microRNA levels and insulin secretion in human pancreatic islets

Author:
  • Elin Hall
  • Petr Volkov
  • Tasnim Dayeh
  • Jonathan Esguerra
  • Sofia Salo
  • Lena Eliasson
  • Tina Rönn
  • Karl Bacos
  • Charlotte Ling
Publishing year: 2014
Language: English
Publication/Series: GenomeBiology
Volume: 15
Issue: 12
Document type: Journal article
Publisher: BioMed Central

Abstract english

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.

Keywords

  • Endocrinology and Diabetes

Other

Published
  • Diabetes and Endocrinology
  • Islet cell exocytosis
  • Molecular Metabolism
  • ISSN: 1465-6906
Tina Rönn
E-mail: tina [dot] ronn [at] med [dot] lu [dot] se

Assistant researcher

Epigenetics and Diabetes

+46 40 39 12 18

CRC 91-12-021

33

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00