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

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.

SUBMITTER: Kokosar M

PROVIDER: S-EPMC4791632 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Kokosar Milana M Benrick Anna A Perfilyev Alexander A Fornes Romina R Nilsson Emma E Maliqueo Manuel M Behre Carl Johan CJ Sazonova Antonina A Ohlsson Claes C Ling Charlotte C Stener-Victorin Elisabet E

Scientific reports 20160315

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), an ...[more]

PMID: 26975253

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Project description:Polycystic ovary syndrome (PCOS) is a chronic metabolic disease that is associated with obesity and adipose tissue dysfunction. This study aimed to explore the roles of Dicer (an enzyme that processes primary microRNAs) and microRNAs in PCOS. Protein levels were detected by western blotting, and mRNA and microRNA levels were detected by RT-PCR. Dicer-deficient pre-adipocytes were established by lentiviral transfection, and an miR-223 mimic and miR-223 inhibitor were used to overexpress and inhibit miR-223, respectively. 3T3-L1 cells were induced to differentiate into mature adipocytes by IBMX, insulin, and dexamethasone. The degree of differentiation was determined by oil red O staining. An insulin resistance model was established by exposing mature adipocytes to excessive glucose and insulin. The protein levels of Dicer and Ago2 in adipose tissues of PCOS patients were significantly lower than those in control females. A Dicer-deficient 3T3-L1 cell model was successfully established, whose proliferation was inhibited significantly. Insulin-resistant mature adipocytes expressed significantly less Dicer protein than control cells. The differentiation of Dicer-deficient 3T3-L1 cells and their expression of miR-223 and marker genes associated with adipose differentiation were reduced significantly. Furthermore, 3T3-L1 cells showed a weaker ability to develop into mature adipocytes when miR-223 expression was inhibited. An miR-223 mimic was used to recover the differentiation block induced by Dicer deficiency. This rescued the expression of genes associated with adipose differentiation, although the differentiation block was not efficiently rescued. It is concluded that insulin resistance may contribute to the decreased levels of Dicer protein in adipose tissue of PCOS patients. This suggests that dysfunction of Dicer plays a significant role in obesity of PCOS patients. miR-223 is a key factor in Dicer-regulated adipose differentiation, and other microRNAs may be involved in the process.

Project description:MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally. In women with polycystic ovary syndrome (PCOS), several miRNAs are differentially expressed compared to women without PCOS, suggesting a role for miRNAs in PCOS pathophysiology. Exercise training modulates miRNA abundance and is primary lifestyle intervention for women with PCOS. Accordingly, we measured the expression of eight circulating miRNAs selected a priori along with miRNA expression from gluteal and abdominal adipose tissue (AT) in 12 women with PCOS and 12 women matched for age and body mass index without PCOS. We also determined the miRNA expression "signatures" before and after high-intensity interval training (HIT) in 42 women with PCOS randomized to either: (1) low-volume HIT (LV-HIT, 10 × 1 min work bouts at maximal, sustainable intensity, n = 13); (2) high-volume HIT (HV-HIT, 4 × 4 min work bouts reaching 90-95% of maximal heart rate, n = 14); or (3) non-exercise control (Non-Ex, n = 15). Both HIT groups trained three times/week for 16 weeks. miRNAs were extracted from plasma, gluteal and abdominal AT, and quantified via a customized plate array containing eight miRNAs associated with PCOS and/or exercise training responses. Basal expression of circulating miRNA-27b (c-miR-27b), implicated in fatty acid metabolism, adipocyte differentiation and inflammation, was 1.8-fold higher in women with compared to without PCOS (P = 0.006) despite no difference in gluteal or abdominal AT miR-27b expression. Only the HV-HIT protocol increased peak oxygen uptake (VO2peak L/min; 9%, P = 0.008). There were no changes in body composition. In LV-HIT, but not HV-HIT, the expression of c-miR-27b decreased (0.5-fold, P = 0.007). None of the remaining seven circulating miRNAs changed in LV-HIT, nor was the expression of gluteal or abdominal AT miRNAs altered. Despite increased cardiorespiratory fitness, HV-HIT did not alter the expression of any circulating, gluteal or abdominal AT miRNAs. We conclude that women with PCOS have a higher basal expression of c-miR-27b compared to women without PCOS and that 16 weeks of LV-HIT reduces the expression of this miRNA in women with PCOS. Intense exercise training had little effect on the abundance of the selected miRNAs within subcutaneous AT depots in women with PCOS.

Dataset Information

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

Publications

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

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