Abstract
Polycystic ovary syndrome (PCOS) is typically characterized by a polycystic ovarian morphology, hyperandrogenism, ovulatory dysfunction, and infertility. Furthermore, PCOS patients undergoing ovarian stimulation have more oocytes; however, the poor quality of oocytes leads to lower fertilization and implantation rates, decreased pregnancy rates, and increased miscarriage rates. The complex molecular mechanisms underlying PCOS and the poor quality of oocytes remain to be elucidated. We obtained matched oocytes and cumulus cells (CCs) from PCOS patients, compared them with age-matched controls, and performed RNA sequencing analysis to explore the transcriptional characteristics of their oocytes and CCs. Moreover, we validated our newly confirmed candidate genes for PCOS by immunofluorescence. Unsupervised clustering analysis showed that the overall global gene expression patterns and transposable element (TE) expression profiles of PCOS patients tightly clustered together, clearly distinct from those of controls. Abnormalities in functionally important pathways are found in PCOS oocytes. Notably, genes involved in microtubule processes, TUBB8 and TUBA1C, are overexpressed in PCOS oocytes. The metabolic and oxidative phosphorylation pathways are also dysregulated in both oocytes and CCs from PCOS patients. Moreover, in oocytes, differentially expressed TEs are not uniformly dispersed in human chromosomes. Endogenous retrovirus 1 (ERV1) elements located on chromosomes 2, 3, 4, and 5 are rather highly upregulated. Interestingly, these correlate with the most highly expressed protein-coding genes, including tubulin-associated genes TUBA1C, TUBB8P8, and TUBB8, linking the ERV1 elements to the occurrence of PCOS. Our comprehensive analysis of gene expression in oocytes and CCs, including TE expression, revealed the specific molecular features of PCOS. The aberrantly elevated expression of TUBB8 and TUBA1C and ERV1 provides additional markers for PCOS and may contribute to the compromised oocyte developmental competence in PCOS patients. Our findings may also have implications for treatment strategies to improve oocyte maturation and the pregnancy outcomes for women with PCOS.
Highlights
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age, with a prevalence of about 10% (March et al, 2010)
By counting the proportion of differentially expressed transposable element (TE) on each chromosome according to the classification of the classes and super-families, we found out the super-families significantly enriched and upregulated in PCOS oocytes and calculated the average normalized expression of the super-families in each oocyte (Ti)
After quality control and filtration of the RNA-seq data, we identified 24,251 genes expressed in oocytes and 42,725 genes in cumulus cells (CCs) samples
Summary
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age, with a prevalence of about 10% (March et al, 2010). Previous genome-wide association study (GWAS) analysis identified 11 loci associated with PCOS and candidate genes at these loci, which were related to the clinical manifestations of PCOS, such as infertility, insulin resistance, T2D, and others (Chen et al, 2011; Shi et al, 2012). These studies facilitated an understanding of the etiologic factors accounting for PCOS. Studies focused on ovarian somatic cells or ovary and other tissues revealed the metabolic abnormalities in PCOS (Ma et al, 2007; Corton et al, 2008; Huang et al, 2010; Zhao et al, 2017; Sanchez-Garrido and Tena-Sempere, 2020). The status of metabolism in the oocytes of PCOS patients remains elusive
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