Dataset Information

Androgen receptor function links human sexual dimorphism to DNA methylation.

ABSTRACT: Sex differences are well known to be determinants of development, health and disease. Epigenetic mechanisms are also known to differ between men and women through X-inactivation in females. We hypothesized that epigenetic sex differences may also result from sex hormone functions, in particular from long-lasting androgen programming. We aimed at investigating whether inactivation of the androgen receptor, the key regulator of normal male sex development, is associated with differences of the patterns of DNA methylation marks in genital tissues. To this end, we performed large scale array-based analysis of gene methylation profiles on genomic DNA from labioscrotal skin fibroblasts of 8 males and 26 individuals with androgen insensitivity syndrome (AIS) due to inactivating androgen receptor gene mutations. By this approach we identified differential methylation of 167 CpG loci representing 162 unique human genes. These were significantly enriched for androgen target genes and low CpG content promoter genes. Additional 75 genes showed a significant increase of heterogeneity of methylation in AIS compared to a high homogeneity in normal male controls. Our data show that normal and aberrant androgen receptor function is associated with distinct patterns of DNA-methylation marks in genital tissues. These findings support the concept that transcription factor binding to the DNA has an impact on the shape of the DNA methylome. These data which derived from a rare human model suggest that androgen programming of methylation marks contributes to sexual dimorphism in the human which might have considerable impact on the manifestation of sex-associated phenotypes and diseases.

SUBMITTER: Ammerpohl O

PROVIDER: S-EPMC3762730 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Androgen receptor function links human sexual dimorphism to DNA methylation.

Ammerpohl Ole O Bens Susanne S Appari Mahesh M Werner Ralf R Korn Bernhard B Drop Stenvert L S SL Verheijen Frans F van der Zwan Yvonne Y Bunch Trevor T Hughes Ieuan I Cools Martine M Riepe Felix G FG Hiort Olaf O Siebert Reiner R Holterhus Paul-Martin PM

PloS one 20130904 9

Sex differences are well known to be determinants of development, health and disease. Epigenetic mechanisms are also known to differ between men and women through X-inactivation in females. We hypothesized that epigenetic sex differences may also result from sex hormone functions, in particular from long-lasting androgen programming. We aimed at investigating whether inactivation of the androgen receptor, the key regulator of normal male sex development, is associated with differences of the pat ...[more]

PMID: 24023855

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Project description:To decipher hormonal from chromosomal factors we compared DNA-methylation of 27,568 CpG-loci in genital fibroblasts from 46,XY feminized individuals (AIS) with inactivating androgen receptor mutations to those of normal males. The results of the following two subset comparisons are linked to the Series record below: CpG loci differentially methylated (q<0.04) between AIS and male controls (primary human genital fibroblasts): To decipher hormonal from chromosomal factors we compared DNA-methylation of 27,568 CpG-loci in genital fibroblasts from 46,XY feminized individuals (AIS) with inactivating androgen receptor mutations to those of normal males. Cell culture of primary fibroblasts from scrotum/ labia majora from donors with PAIS (n=13), MAIS (n=1) or CAIS (n=13) and 9 controls were analyzed using the HumanMethylation27 Bead Chip. 13 AIS samples and all controls were analyzed in duplicates. Samples with gene call rates <95% as analyzed with BeadStudio software (Illumina, Inc.) and CpGs with detection p-values >0.05 in at least one experiment were excluded from analyses. 54 hybridizations with 25,988 CpGs entered the analysis. Differential methylation analysis (DMA) was performed based on average beta-values were performed using OMICS Explorer (v.2.1(25); Qlucore, Sweden). This file contains CpG loci found differentially methylated (q<0.04) by this approach. CpG loci characterized by a high varibility in their DNA methylation value in AIS compared to male controls (primary human genital fibroblasts): To decipher hormonal from chromosomal factors we compared DNA-methylation of 27,568 CpG-loci in genital fibroblasts from 46,XY feminized individuals (AIS) with inactivating androgen receptor mutations to those of normal males. Cell culture of primary fibroblasts from scrotum/ labia majora from donors with PAIS (n=13), MAIS (n=1) or CAIS (n=13) and 9 controls were analyzed using the HumanMethylation27 Bead Chip. 13 AIS samples and all controls were analyzed in duplicates. Samples with gene call rates <95% as analyzed with BeadStudio software (Illumina, Inc.) and CpGs with detection p-values >0.05 in at least one experiment were excluded from analyses. 54 hybridizations with 25,988 CpGs entered the analysis. CpG loci with beta-values ranged in control samples up to 0.34 and a difference of the interquartiles between controls and AIS samples above 0.16 were considered as being variably methylated in AIS and are included in this file.

Dataset Information

Androgen receptor function links human sexual dimorphism to DNA methylation.

Publications

Androgen receptor function links human sexual dimorphism to DNA methylation.

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