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. 2016 Mar 15:6:22883.
doi: 10.1038/srep22883.

Epigenetic and Transcriptional Alterations in Human Adipose Tissue of Polycystic Ovary Syndrome

Milana Kokosar  1 , Anna Benrick  1 , Alexander Perfilyev  2 , Romina Fornes  3 , Emma Nilsson  2 , Manuel Maliqueo  3   4 , Carl Johan Behre  5 , Antonina Sazonova  6 , Claes Ohlsson  7 , Charlotte Ling  2 , Elisabet Stener-Victorin  3
Affiliations

Epigenetic and Transcriptional Alterations in Human Adipose Tissue of Polycystic Ovary Syndrome

Milana Kokosar et al. Sci Rep. .

Erratum in

Abstract

Genetic and epigenetic factors may predispose women to polycystic ovary syndrome (PCOS), a common heritable disorder of unclear etiology. Here we investigated differences in genome-wide gene expression and DNA methylation in adipose tissue from 64 women with PCOS and 30 controls. In total, 1720 unique genes were differentially expressed (Q < 0.05). Six out of twenty selected genes with largest expression difference (CYP1B1, GPT), genes linked to PCOS (RAB5B) or type 2 diabetes (PPARG, SVEP1), and methylation (DMAP1) were replicated in a separate case-control study. In total, 63,213 sites (P < 0.05) and 440 sites (Q < 0.15) were differently methylated. Thirty differentially expressed genes had corresponding changes in 33 different DNA methylation sites. Moreover, a total number of 1913 pairs of differentially expressed "gene-CpG" probes were significantly correlated after correction for multiple testing and corresponded with 349 unique genes. In conclusion, we identified a large number of genes and pathways that are affected in adipose tissue from women with PCOS. We also identified specific DNA methylation pathways that may affect mRNA expression. Together, these novel findings show that women with PCOS have multiple transcriptional and epigenetic changes in adipose tissue that are relevant for development of the disease.

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Figures

Figure 1
Figure 1. Gene sets contributing to selected significant top canonical pathways, identified by Ingenuity Pathway Analysis, of possible relevance to PCOS and T2D.
Up-regulated canonical pathways: (A) PI3K/AKT Signaling pathway, (B) ERK/MAPK signaling pathway, (C) Androgen receptor signaling pathway, (D) TGF-β signaling pathway, (E) IGF1-1 signaling pathway, (F) NGF signaling pathway, and (G) Telomerase signaling pathway. Down-regulated canonical pathway: (H) NRF2-mediated oxidative stress response signaling pathway. Values are mean ± SD. *P < 0.05.
Figure 2
Figure 2. Selected genes relevant to PCOS that were differentially expressed in cohort 1 and replicated in cohort 2.
(A) Expression data of selected genes from the Illumina HumanHT- 12 v4 Expression BeadChip array (cohort 1). (B) Replication of gene expression data from the array by qPCR in adipose tissue from 21 unrelated women with PCOS and 21 controls (cohort 2). Protein expression of CYP1B1 (C) and PPARG (D) in control (n=5) and PCOS (n=5) are presented. (E) Differential DNA methylation of biologically validated genes. Values for gene expression are mean ± SD and for proteins mean ± SEM. *P < 0.05 (*) P = 0.056. # Sample run on a different membrane.
Figure 3
Figure 3. Effect of PCOS on global DNA methylation in human adipose tissue.
Global DNA methylation was calculated as the average DNA methylation of all CpG sites in each annotated region on the Infinium Human Methylation 450 BeadChip presented for (A) the nearest gene region and (B) nearest CpG island region (mean ± SD). Absolute difference in DNA methylation of 63,213 individual sites divided into (C) sites with less methylation and (D) sites with more methylation in 64 women with PCOS than in 30 controls (cohort 1). Distribution of significant sites compared with all analyzed sites in relation to nearest gene region (E) and nearest CpG island region (F). TSS, proximal promotor defined as 200 or 1500 bp upstream of the transcription site; Shore, flanking region of CpG island (0–2000 bp); Shelf, regions flanking island shores (2000–4000 bp from the CpG island).
Figure 4
Figure 4. Representative illustrations of correlations of gene expression with DNA methylation in adipose tissue from cohort 1.
Expression CD74 correlated positively with DNA methylation (A); BCKDHA correlated negatively with DNA methylation (B); GPT correlated positively with DNA methylation (C); and PPARG correlated negatively with DNA methylation (D). Spearman rank correlation with FDR corrections.
Figure 5
Figure 5. Correlations of GDR, adipocyte size, and circulating testosterone level with gene expression in adipose tissue from cohort 1.
Expression of GPT correlated positively with GDR (A), negatively with circulating testosterone (B), and with adipocyte volume (C); RTN4 correlated negatively with GDR (D), positively with testosterone (E), and with adipocyte volume (F); BCKDHA correlated positively with GDR (G), negatively with circulating testosterone (H), and with adipocyte volume (I); CD74 correlated positively with circulating testosterone (J); DMPA1 correlated negatively with circulating testosterone (K); and SVEP1 correlated positively with adipocyte volume (L). Pearson’s partial correlation.
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