Abstract
Steroid synthesis and metabolic pathways play important roles in the pathophysiology of PCOS, but until now there have been no studies on the methylation profiles of specific genes in steroid synthesis pathways that are known to be associated with PCOS. Here we used MassARRAY quantitative methylation analysis to determine the methylation levels of each CpG site or cluster in the promoters of EPHX1, SRD5A1, and CYP11A1 in 64 peripheral blood samples. We further examined the methylation level of EPHX1 in an independent cohort consisting of 116 people. Finally, we investigated the role of EPHX1 in steroidogenesis in the KGN cell line. For SRD5A1 and CYP11A1, there was no significant difference in methylation level between patients and controls. For EPHX1, however, the methylation levels of a few consecutive CpG sites and clusters were found to be significantly associated with PCOS. The methylation levels of a number of CpG clusters or sites were significantly lower in patients than in controls in the first cohort consisting of 64 people, such as clusters 13–14 (P<0.05), 15–16 (P<0.001), and 19–24 (P<0.001) and sites CpG_53 (P<0.01) and CpG_54 (P<0.05). Among differentiated methylation sites and clusters, the methylation levels of the CpG cluster 13–14 and CpG cluster 19–24 in PCOS patients were significantly lower than in controls in the second cohort of 116 people (P<0.05 for both). In addition, knockdown and overexpression experiments in KGN cells showed that EPHX1 can regulate estradiol concentrations, and this indicates a role for EPHX1 in steroidogenesis. Our study has demonstrated that methylation of the EPHX1 promoter might be associated with PCOS. This study provides direct evidence that methylation plays an important role in PCOS and demonstrates a novel role for EPHX1 in female reproduction.
Highlights
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-age women and has an estimated global prevalence of approximately 5%–10%
For SRD5A1 and CYP11A1, there were no significant difference in methylation of any promoter CpG site or cluster between PCOS patients and healthy women (Figure S1)
Recent advances in epigenetics and epigenomics have provided evidence that epigenetic mechanisms may function as an interface between environmental factors and the genome [22]
Summary
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-age women and has an estimated global prevalence of approximately 5%–10%. It is a leading cause of female infertility and is associated with polycystic ovaries, hirsutism, obesity, and insulin resistance [1,2]. Xu et al performed pioneering work on the global DNA methylation status of peripheral blood from PCOS patients and healthy women. We recently investigated the methylation level of follistatin in the peripheral blood of patients with PCOS but did not find any difference compared to the methylation level in controls [11]
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