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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.

Hall E, Volkov P, Dayeh T, Esguerra JL, Salö S, Eliasson L, Rönn T, Bacos K, Ling C - Genome Biol. (2014)

Bottom Line: 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.Differential methylation between sexes is associated with altered levels of microRNAs miR-660 and miR-532 and related target genes.Our data demonstrate that epigenetics contribute to sex-specific metabolic phenotypes.

View Article: PubMed Central - PubMed

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.

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Impact of sex on DNA methylation and/or expression in human pancreatic islets of selected candidate genes. (A)DUSP9, a candidate gene for type 2 diabetes, is located on the X chromosome and has numerous differentially methylated CpG sites between female and male human pancreatic islets. (B-D) Impact of sex on the DNA methylation level of CpG sites and gene expression of NKAP(B), APLN(C) and SPESP1(D). Data are presented as mean ± standard error of the mean. Asterisks indicate q <0.05 for DNA methylation and P <0.05 for expression
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Fig4: Impact of sex on DNA methylation and/or expression in human pancreatic islets of selected candidate genes. (A)DUSP9, a candidate gene for type 2 diabetes, is located on the X chromosome and has numerous differentially methylated CpG sites between female and male human pancreatic islets. (B-D) Impact of sex on the DNA methylation level of CpG sites and gene expression of NKAP(B), APLN(C) and SPESP1(D). Data are presented as mean ± standard error of the mean. Asterisks indicate q <0.05 for DNA methylation and P <0.05 for expression

Mentions: Genome-wide association study (GWAS) data point to islet defects as key mechanisms in the development of type 2 diabetes and suggest that there are sex differences in the genetic predisposition to diabetes and related metabolic traits [26,27]. We therefore tested if there are sex differences in the degree of DNA methylation of candidate genes for type 2 diabetes and related traits in human pancreatic islets, which may contribute to altered metabolism and affect the risk for disease. We used gene lists of candidate genes for type 2 diabetes, and candidate genes for type 2 diabetes-related traits based on the online catalog of published GWAS [28]. Included genes had a P-value threshold for GWAS SNP finding at P <10-5. In total, the type 2 diabetes candidate gene list included 100 genes and 79 candidate genes for related traits. Sites annotated to 10 candidate genes for type 2 diabetes, including DUSP9, BCL11A, HNF4A, and CDKN2B, and 7 candidate genes for related metabolic traits (for example, ATP11A, ADCY5 and IRS1) had differential DNA methylation in human pancreatic islets based on sex (Additional files 11 and 12). Interestingly, DUSP9 is located on the X chromosome and had 16 CpG sites with an absolute difference in DNA methylation of more than 5% between males and females (Figure 4A).Figure 4


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

Hall E, Volkov P, Dayeh T, Esguerra JL, Salö S, Eliasson L, Rönn T, Bacos K, Ling C - Genome Biol. (2014)

Impact of sex on DNA methylation and/or expression in human pancreatic islets of selected candidate genes. (A)DUSP9, a candidate gene for type 2 diabetes, is located on the X chromosome and has numerous differentially methylated CpG sites between female and male human pancreatic islets. (B-D) Impact of sex on the DNA methylation level of CpG sites and gene expression of NKAP(B), APLN(C) and SPESP1(D). Data are presented as mean ± standard error of the mean. Asterisks indicate q <0.05 for DNA methylation and P <0.05 for expression
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4256841&req=5

Fig4: Impact of sex on DNA methylation and/or expression in human pancreatic islets of selected candidate genes. (A)DUSP9, a candidate gene for type 2 diabetes, is located on the X chromosome and has numerous differentially methylated CpG sites between female and male human pancreatic islets. (B-D) Impact of sex on the DNA methylation level of CpG sites and gene expression of NKAP(B), APLN(C) and SPESP1(D). Data are presented as mean ± standard error of the mean. Asterisks indicate q <0.05 for DNA methylation and P <0.05 for expression
Mentions: Genome-wide association study (GWAS) data point to islet defects as key mechanisms in the development of type 2 diabetes and suggest that there are sex differences in the genetic predisposition to diabetes and related metabolic traits [26,27]. We therefore tested if there are sex differences in the degree of DNA methylation of candidate genes for type 2 diabetes and related traits in human pancreatic islets, which may contribute to altered metabolism and affect the risk for disease. We used gene lists of candidate genes for type 2 diabetes, and candidate genes for type 2 diabetes-related traits based on the online catalog of published GWAS [28]. Included genes had a P-value threshold for GWAS SNP finding at P <10-5. In total, the type 2 diabetes candidate gene list included 100 genes and 79 candidate genes for related traits. Sites annotated to 10 candidate genes for type 2 diabetes, including DUSP9, BCL11A, HNF4A, and CDKN2B, and 7 candidate genes for related metabolic traits (for example, ATP11A, ADCY5 and IRS1) had differential DNA methylation in human pancreatic islets based on sex (Additional files 11 and 12). Interestingly, DUSP9 is located on the X chromosome and had 16 CpG sites with an absolute difference in DNA methylation of more than 5% between males and females (Figure 4A).Figure 4

Bottom Line: 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.Differential methylation between sexes is associated with altered levels of microRNAs miR-660 and miR-532 and related target genes.Our data demonstrate that epigenetics contribute to sex-specific metabolic phenotypes.

View Article: PubMed Central - PubMed

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.

Show MeSH
Related in: MedlinePlus