Altered DNA methylation and miRNA expression: epi-marks for elucidating the pathophysiology of PCOS

Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrinopathy affecting women of reproductive age. This multifactorial disorder is characterized by oligo- or amenorrhoea, clinical and biochemical signs of hyperandrogenism, polycystic ovarian morphology on ultrasound, and impaired fertility. Beyond reproductive challenges, PCOS is associated with elevated risks of metabolic disturbances and associated comorbidities including insulin resistance, obesity, hypertension, type 2 diabetes and cardiovascular diseases. Despite extensive research, the pathophysiology of PCOS remains elusive. Advances in high-throughput sequencing and molecular biology techniques reflect the tandem influence of both genetic and epigenetic factors in its pathogenesis. Notably, the absence of strong genetic determinants and growing evidence implicating intrauterine and lifestyle-associated factors strongly support the epigenetic model of inheritance and development of PCOS. The epigenetic machinery, through mechanisms including DNA and RNA methylation and histone modifications, regulates gene expression and chromatin structure. Recent studies have identified small non-coding RNA and particularly microRNAs (miRNAs) as additional epigenetic components that modulate transcriptional silencing by interacting with target mRNA. Together, these epigenetic mechanisms impact tissue-specific gene expression patterns and, hence, potential to trigger disease development. Changes in global and tissue-specific DNA methylation and miRNA expression patterns have been studied extensively in the context of the pathophysiology of PCOS. Many of these changes have been linked to metabolic and ovarian dysregulation associated with this condition. This review highlights recent advances in understanding the epigenetic landscape of PCOS, focusing on DNA methylation and changes in miRNA expression, and discusses their implications on mechanisms underlying the development of PCOS.