Identification of epigenetic interactions between microRNA and DNA methylation associated with polycystic ovarian syndrome

Abstract

Aberration in microRNA expression or DNA methylation is a causal factor for polycystic ovarian syndrome. However, the epigenetic interactions between miRNA and DNA methylation remain unexplored in PCOS. We conducted a novel integrated analysis of RNA-seq, miRNA-seq, and methylated DNA-binding domain sequencing on ovarian granulosa cells to reveal the epigenetic interactions involved in the pathogenesis of PCOS. We identified 830 genes and 30 miRNAs that were expressed differently in PCOS, and seven miRNAs negatively regulated target mRNA expression. 130 miRNAs' promoters were significantly differently methylated, while 13 were associated with miRNA expression. Furthermore, the hypermethylation of miR-429, miR-141-3p, and miR-126-3p′ promoter was found related to miRNA expression suppression and therefore their corresponding genes upregulation, including XIAP, BRD3, MAPK14, and SLC7A5. Our findings provide a novel insight in PCOS. The consequential reversal of genes silencing may participate in PCOS pathogenesis and served as potential molecular targets for PCOS.

Characterization of micro-RNA in women with different ovarian reserve

“…Regulation of miR-140-5p by the Estrogen receptor α ( ERα ) was detected in women with breast cancer and in women with PCOS 27 , 28 . Similarly, miR-126-3p was also associated with PCOS 29 . The hypermethylation in the promoter site of the miR-126-3p gene was found in granulosa cells of patients with PCOS, which resulted in a reduction of the abundance level of miR-126-3p 29 .…”

Polycystic Ovary Syndrome: A Brain Disorder Characterized by Eating Problems Originating during Puberty and Adolescence

“…These observations indicate common underlying signaling networks involved both in the etiology and heterogeneity of PCOS including pathways linked to mitochondrial metabolism [118]. It is important to note that underlying epigenetic mechanisms extend beyond covalent modifications to histones and DNA depicted in Figure 3 to include interacting long non-coding and microRNAs that are known to influence DNA methylation in PCOS [119]. These are also metabolically regulated [80] and are associated with insulin resistance and lipid disorders in PCOS women [120].…”

Characterization of DNA Methylation and Screening of Epigenetic Markers in Polycystic Ovary Syndrome

“…We identified several key genes, such as IRS1, KLF5, CYP1B1, ETS1, and BMP4, and some signaling pathways including steroid metabolic process, response to insulin, female pregnancy, estrous cycle, and fat cell differentiation. The alternation of these genes’ expression and signaling pathways could contribute to the symptoms of PCOS, such as the type 2 diabetes, infertility, hormonal disorders, and obesity ( Combs et al, 2021 ; Mao et al, 2021 ). Additionally, we found some DEGs were significantly enriched in circadian rhythm signaling pathway ( Figure 1E ), suggesting that insomnia observed in some of the PCOS patients might be due to the expression changes of these genes.…”

“…The data used in this study was downloaded from Gene Expression Omnibus (GEO) ( Mao et al, 2021 ). The RNA-seq data were obtained under accession number GEO: GSE155489 .…”

“…The pairwise interaction genes in the DNA hypomethylation regulated gene modules were defined as seed nodes, and the Pearson correlation coefficient was used as the weight of the edges. By combining the background PPI network and the co-expression networks composed of the seed nodes, two gene co-expression networks of candidate markers were obtained ( Mao et al, 2021 ). MCODE application was used for models mining.…”