Androgen Receptor Function Links Human Sexual Dimorphism to DNA Methylation

Ammerpohl, Ole; Bens, Susanne; Appari, Mahesh; Werner, Ralf; Korn, Bernhard; Drop, Stenvert L. S.; Verheijen, Frans W.; Zwan, Yvonne van der; Bunch, Trevor; Hughes, Ieuan A.; Cools, Martine; Riepe, Felix G.; Hiort, Olaf; Siebert, Reiner; Holterhus, Paul‐Martin

doi:10.1371/journal.pone.0073288

Cited by 27 publications

(18 citation statements)

References 52 publications

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“…71 Some of the autosomal sex-DMGs, such as TLE1 and NUPL1, found by both us and Liu et al could already be detected in samples from umbilical cord blood at time of birth. 66,72 However, sex-specific methylation has been shown to be modified by sex hormones, 23,69 as suggested also from preliminary studies showing hormonerelated changes in DNA methyltransferase expression during menstrual cycles or pregnancy in the uterus, 59,73 indicating that the mechanism of sex differences in CpG methylation is complex and dynamic. Compared to immune cell subset-specific DMGs, autosomal sex-specific DMGs were much more common in CGIs, suggesting some difference in the mechanisms of sex-related vs. immune cell-specific regulation; however, in both cases, the DMGs were mainly found in the gene body.…”

Section: Discussionmentioning

confidence: 99%

“…13,18 Sexual dimorphism is established early in development and reinforced in adults by hormonal regulation, which is in part regulated by DNA methylation. [23][24][25] Sex is a known factor affecting the methylation pattern mainly on the X chromosome, but also on autosomal chromosomes. 26,27 The general prevalence, course, and severity of several diseases, including autoimmune diseases, are higher in females compared to males.…”

Section: Introductionmentioning

confidence: 99%

“…26,27 The general prevalence, course, and severity of several diseases, including autoimmune diseases, are higher in females compared to males. 23,28,29 This sex bias could be due to sex-specific hormones or to differences between male and female immune responses. 28 Females have been shown to produce stronger humoral and cellular immune responses to antigen than males, suggesting that this increased immune reactivity makes women more prone to develop autoimmune diseases.…”

Section: Introductionmentioning

confidence: 99%

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Integrative analysis of methylome and transcriptome in human blood identifies extensive sex- and immune cell-specific differentially methylated regions

et al. 2015

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The relationship between DNA methylation and gene expression is complex and elusive. To further elucidate these relations, we performed an integrative analysis of the methylome and transcriptome of 4 circulating immune cell subsets (B cells, monocytes, CD4(+), and CD8(+) T cells) from healthy females. Additionally, in light of the known sex bias in the prevalence of several immune-mediated diseases, the female datasets were compared with similar public available male data sets. Immune cell-specific differentially methylated regions (DMRs) were found to be highly similar between sexes, with an average correlation coefficient of 0.82; however, numerous sex-specific DMRs, shared by the cell subsets, were identified, mainly on autosomal chromosomes. This provides a list of highly interesting candidate genes to be studied in disorders with sexual dimorphism, such as autoimmune diseases. Immune cell-specific DMRs were mainly located in the gene body and intergenic region, distant from CpG islands but overlapping with enhancer elements, indicating that distal regulatory elements are important in immune cell specificity. In contrast, sex-specific DMRs were overrepresented in CpG islands, suggesting that the epigenetic regulatory mechanisms of sex and immune cell specificity may differ. Both positive and, more frequently, negative correlations between subset-specific expression and methylation were observed, and cell-specific DMRs of both interactions were associated with similar biological pathways, while sex-specific DMRs were linked to networks of early development or estrogen receptor and immune-related molecules. Our findings of immune cell- and sex-specific methylome and transcriptome profiles provide novel insight on their complex regulatory interactions and may particularly contribute to research of immune-mediated diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Integrative analysis of methylome and transcriptome in human blood identifies extensive sex- and immune cell-specific differentially methylated regions

et al. 2015

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“…This type of regulatory cascade may then affect low-order complex traits, such as metabolism (26) and DNA methylation (27), or higher-order complex traits, such as disease susceptibility (1,10,11).…”

Section: Introductionmentioning

confidence: 99%

Tissue-specific sex differences in human gene expression

Kassam

Yang

et al. 2019

Human Molecular Genetics

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Despite extensive sex differences in human complex traits and disease, the male and female genomes differ only in the sex chromosomes. This implies that most sex-differentiated traits are the result of differences in the expression of genes that are common to both sexes. While sex differences in gene expression have been observed in a range of different tissues, the biological mechanisms for tissue-specific sex differences (TSSDs) in gene expression are not well understood. A total of 30 640 autosomal and 1021 X-linked transcripts were tested for heterogeneity in sex difference effect sizes in n = 617 individuals across 40 tissue types in Genotype–Tissue Expression (GTEx). This identified 65 autosomal and 66 X-linked TSSD transcripts (corresponding to unique genes) at a stringent significance threshold. Results for X-linked TSSD transcripts showed mainly concordant direction of sex differences across tissues and replicate previous findings. Autosomal TSSD transcripts had mainly discordant direction of sex differences across tissues. The top cis-expression quantitative trait loci (eQTLs) across tissues for autosomal TSSD transcripts are located a similar distance away from the nearest androgen and estrogen binding motifs and the nearest enhancer, as compared to cis-eQTLs for transcripts with stable sex differences in gene expression across tissue types. Enhancer regions that overlap top cis-eQTLs for TSSD transcripts, however, were found to be more dispersed across tissues. These observations suggest that androgen and estrogen regulatory elements in a cis region may play a common role in sex differences in gene expression, but TSSD in gene expression may additionally be due to causal variants located in tissue-specific enhancer regions.

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“…Determination of gene expression patterns involves epigenetic modifications, including DNA-methylation [ 16 , 17 ]. For hormones other than GH it has been shown that transcriptional effects induced by these hormones are conferred or at least accompanied by DNA-methylation changes [ 18 , 19 , 20 ]. Altered DNA-methylation is also a feature of many diseases, including diabetes and cancer [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

In vivo Investigations of the Effect of Short- and Long-Term Recombinant Growth Hormone Treatment on DNA-Methylation in Humans

et al. 2015

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Treatment with recombinant human growth hormone (rhGH) has been consistently reported to induce transcriptional changes in various human tissues including peripheral blood. For other hormones it has been shown that the induction of such transcriptional effects is conferred or at least accompanied by DNA-methylation changes. To analyse effects of short term rhGH treatment on the DNA-methylome we investigated a total of 24 patients at baseline and after 4-day rhGH stimulation. We performed array-based DNA-methylation profiling of paired peripheral blood mononuclear cell samples followed by targeted validation using bisulfite pyrosequencing. Unsupervised analysis of DNA-methylation in this short-term treated cohort revealed clustering according to individuals rather than treatment. Supervised analysis identified 239 CpGs as significantly differentially methylated between baseline and rhGH-stimulated samples (p<0.0001, unadjusted paired t-test), which nevertheless did not retain significance after adjustment for multiple testing. An individualized evaluation strategy led to the identification of 2350 CpG and 3 CpH sites showing methylation differences of at least 10% in more than 2 of the 24 analyzed sample pairs. To investigate the long term effects of rhGH treatment on the DNA-methylome, we analyzed peripheral blood cells from an independent cohort of 36 rhGH treated children born small for gestational age (SGA) as compared to 18 untreated controls. Median treatment interval was 33 months. In line with the groupwise comparison in the short-term treated cohort no differentially methylated targets reached the level of significance in the long-term treated cohort. We identified marked intra-individual responses of DNA-methylation to short-term rhGH treatment. These responses seem to be predominately associated with immunologic functions and show considerable inter-individual heterogeneity. The latter is likely the cause for the lack of a rhGH induced homogeneous DNA-methylation signature after short- and long-term treatment, which nevertheless is well in line with generally assumed safety of rhGH treatment.

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Androgen Receptor Function Links Human Sexual Dimorphism to DNA Methylation

Cited by 27 publications

References 52 publications

Integrative analysis of methylome and transcriptome in human blood identifies extensive sex- and immune cell-specific differentially methylated regions

Integrative analysis of methylome and transcriptome in human blood identifies extensive sex- and immune cell-specific differentially methylated regions

Tissue-specific sex differences in human gene expression

In vivo Investigations of the Effect of Short- and Long-Term Recombinant Growth Hormone Treatment on DNA-Methylation in Humans

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