Identification of Epigenetic Interactions between MicroRNA and DNA Methylation Associated with Polycystic Ovarian Syndrome

Abstract

Aberration in microRNA (miRNA) expression or DNA methylation is a causal factor for polycystic ovarian syndrome (PCOS), a common endocrine disorder and leading cause of infertility. However, the epigenetic interactions between miRNA and DNA methylation remain unexplored in PCOS. In this study, we conducted an integrated analysis of RNA-seq, miRNA-seq and MBD-seq on ovarian granulosa cells of PCOS and control groups to reveal the epigenetic interactions involved in the pathogenesis of PCOS. Firstly, we identified 830 genes and 30 miRNAs that were expressed differently in PCOS, and seven miRNAs were found to negatively regulate targeted mRNA expression. Next, in total, 130 miRNAs were found to be significantly differently methylated in promoter regions, while 13 were found to be associated with miRNA expression. Furthermore, the promoter hypermethylation of miR-429, miR-141-3p, and miR-126-3p was proven to suppress miRNA expression and therefore upregulate their corresponding genes, including XIAP, BRD3, MAPK14 and SLC7A5. Our results demonstrate that DNA methylation regulates miRNA expression and therefore controls its corresponding gene expression. The reactivation of the transcription of epigenetically silenced genes may be one of the key elements in PCOS pathogenesis. Meanwhile, the epigenetic mechanisms underlying the regulation of miRNA expression can provide a potential therapeutic target for PCOS in the future.

Aberrant miRNA-mRNA regulatory network in polycystic ovary syndrome is associated with markers of insulin sensitivity and inflammation

“…STAT1 was reported to be related to inflammation and insulin sensitivity in adipose tissue and obesity (40). MAPK14 has a wide effect on regulating inflammation and metabolism, and was shown to be regulated by miRNA epigenetics in PCOS in our previous study (24). CSF1R was a key gene in leukoencephalopathy (41).…”

“…xlsx). The potential target mRNAs were mapped to our previous RNA-seq data of GCs from women with PCOS and the control group (24). Finally, we screened out one upregulated target gene of miR-106a-5p (RUNX1) and five upregulated target genes of miR-155-5p (CSF1R, FOS, MAPK14, SPI1, and STAT1) from the DEGs identified in our previous data (Table 3).…”

Long non-coding RNA NEAT1 deteriorates polycystic ovary syndrome progression via binding microRNA-324-3p to target bromodomain containing 3

“…As predicated by the bioinformatic website, BRD3 was a target gene of miR-324-3p. BRD3 has been clari ed to be enriched in ovarian granulosa cells in PCOS [13]. Functionally, the ablation of BRD3 can decelerate the viability of ovarian clear cell carcinoma [14].…”

“…The bioinformatic website also predicated that there was a binding relation between miR-324-3p and target bromodomain containing 3 (BRD3). Encoded by paralogous genes, Belonging to bromodomain and extra-terminal domain family [12], BRD3 also exhibits high expression in ovarian granulosa cells of PCOS [13]. Furthermore, the silence of BRD3 is responsible for impairing ovarian clear cell carcinoma viability [14].…”

Nutraceutical Treatment of Patients with Polycystic Ovary Syndrome

“…Recently the importance of epigenetic interactions between microRNA and DNA methylation has been highlighted in patients PCOS [31]. Hypermethylation of certain DNA domains was found to play a pivotal role, as it does in many diseases and in carcinogenesis [32].…”