Comprehensive analysis of genome-wide DNA methylation across human polycystic ovary syndrome ovary granulosa cell.

Jiawei Xu,Zhaofeng Peng,Linqing Du,Linlin Wang,Yingpu Sun,Wenbin Niu,Xiao Bao

doi:10.18632/oncotarget.8544

Jiawei Xu, Zhaofeng Peng + Show 5 more

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https://doi.org/10.18632/oncotarget.8544

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Abstract

Polycystic ovary syndrome (PCOS) affects approximately 7% of the reproductive-age women. A growing body of evidence indicated that epigenetic mechanisms contributed to the development of PCOS. The role of DNA modification in human PCOS ovary granulosa cell is still unknown in PCOS progression. Global DNA methylation and hydroxymethylation were detected between PCOS’ and controls’ granulosa cell. Genome-wide DNA methylation was profiled to investigate the putative function of DNA methylaiton. Selected genes expressions were analyzed between PCOS’ and controls’ granulosa cell. Our results showed that the granulosa cell global DNA methylation of PCOS patients was significant higher than the controls’. The global DNA hydroxymethylation showed low level and no statistical difference between PCOS and control. 6936 differentially methylated CpG sites were identified between control and PCOS-obesity. 12245 differential methylated CpG sites were detected between control and PCOS-nonobesity group. 5202 methylated CpG sites were significantly differential between PCOS-obesity and PCOS-nonobesity group. Our results showed that DNA methylation not hydroxymethylation altered genome-wide in PCOS granulosa cell. The different methylation genes were enriched in development protein, transcription factor activity, alternative splicing, sequence-specific DNA binding and embryonic morphogenesis. YWHAQ, NCF2, DHRS9 and SCNA were up-regulation in PCOS-obesity patients with no significance different between control and PCOS-nonobesity patients, which may be activated by lower DNA methylaiton. Global and genome-wide DNA methylation alteration may contribute to different genes expression and PCOS clinical pathology.

Highlights

Polycystic ovary syndrome (PCOS) is a complex and highly heterogeneous women endocrine disorder, the features include ovarian dysfunction, menstrual disorders, hyperandrogenemia, insulin resistance, abdominal obesity and infertility [1]
Our results showed that the granulosa cell global DNA methylation of PCOS patients was significant higher than the controls’
Different gene expression patterns were detected in human PCOS granulose cell, indicating that PCOS profound affected the function of granulosa cell and may resulted in follicular development abnormal [19, 25, 26], the genetic and environmental roles in the development of the PCOS and dysregulation of gene expression remain unclear

Summary

Introduction

Polycystic ovary syndrome (PCOS) is a complex and highly heterogeneous women endocrine disorder, the features include ovarian dysfunction, menstrual disorders, hyperandrogenemia, insulin resistance, abdominal obesity and infertility [1]. DNA methylation(5mC) as one of the best-studied DNA modification is a major epigenetic modification of the genome generally inhibit gene expression, whereas DNA hydroxymethylation(5hmC) associated with increasing gene expression [7, 8]. Different level in 5mC at single specific loci can be sufficient to regulate gene expression [9]. 5mC changes at specific loci cannot indicate the changes occurring at global levels. The level of 5hmC exhibit rather variable and show tissues and cell types specific [10, 11]. It had been reported that peripheral blood DNA global methylation was not significantly altered in PCOS compared with healthy controls [12]. Whether global DNA methylaiton www.impactjournals.com/oncotarget and hydroxymethylation involved in PCOS development or not was needed to explore

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