Hypomethylation-Triggered SERPINE1 (Serpin Family E Member 1) Exacerbates Polycystic Ovary Syndrome with Hyperandrogenism Induced by Circadian Disruption
Abstract
Polycystic ovary syndrome represents one of the most prevalent and significant causes of female infertility worldwide, affecting millions of women of reproductive age and creating substantial challenges for both patients and healthcare providers. This complex endocrine disorder arises from intricate and multifaceted interactions between genetic predisposition factors and various environmental influences, creating a heterogeneous condition that manifests differently across affected individuals. Among the numerous pathological features that characterize polycystic ovary syndrome, hyperandrogenism stands out as a core and fundamental pathological feature that underlies many of the clinical manifestations observed in this condition, including irregular menstrual cycles, hirsutism, acne, and metabolic disturbances.
The relationship between circadian rhythm disruptions and the development of hyperandrogenism in polycystic ovary syndrome has become an area of increasing scientific interest and investigation. Growing evidence from multiple research studies has established compelling links between various forms of circadian disruptions and the development and progression of hyperandrogenic states characteristic of polycystic ovary syndrome. These disruptions can occur through various mechanisms including shift work, irregular sleep patterns, exposure to artificial light during nighttime hours, and other lifestyle factors that interfere with normal circadian rhythm maintenance. However, despite the accumulating evidence supporting this association, the precise underlying molecular mechanisms through which circadian disruptions contribute to hyperandrogenism development in polycystic ovary syndrome have remained largely unclear and poorly understood.
To address this significant knowledge gap and advance our understanding of the mechanistic connections between circadian disruption and hyperandrogenism, the present comprehensive investigation employed sophisticated molecular profiling techniques including DNA methylation analysis and RNA sequencing methodologies. These advanced genomic approaches were applied to ovarian granulosa cells obtained from experimental rats that had been subjected to eight weeks of continuous darkness exposure, creating a well-controlled model of circadian disruption that allows for detailed mechanistic investigation of the molecular changes that occur in response to altered light-dark cycles.
Through these comprehensive molecular profiling analyses, the research team successfully identified serpin family E member 1, commonly abbreviated as SERPINE1, as a key molecular player in the pathophysiological processes linking circadian disruption to hyperandrogenism development. This identification represents a significant breakthrough in understanding the molecular mechanisms underlying circadian disruption-induced hyperandrogenism and provides important insights into potential therapeutic targets for intervention.
The experimental findings revealed that SERPINE1 exhibited significant hypomethylation patterns and corresponding upregulation in gene expression levels in the experimental group exposed to continuous darkness conditions, compared to control animals maintained under normal light-dark cycles. These molecular changes in SERPINE1 methylation and expression patterns showed strong correlations with elevated androgen hormone levels measured in the same experimental animals, suggesting a direct mechanistic relationship between SERPINE1 dysregulation and hyperandrogenism development.
To further elucidate the precise molecular mechanisms underlying SERPINE1 regulation in this context, the research team employed sophisticated CRISPR-dCas9-based targeted methylation techniques, which allow for precise manipulation of DNA methylation patterns at specific genomic loci. Through these advanced molecular tools, the investigators demonstrated that CpG dinucleotide hypomethylation occurring in close proximity to the SERPINE1 transcription start site served as the primary driving force behind the observed overexpression of this gene. This finding provides crucial mechanistic insights into how epigenetic modifications can directly influence gene expression patterns in response to environmental stimuli such as circadian disruption.
Comprehensive functional assays conducted as part of this investigation revealed important downstream consequences of SERPINE1 dysregulation in the context of androgen metabolism and hormone regulation. Specifically, experimental suppression of SERPINE1 expression resulted in activation of the PI3K/AKT signaling pathway, which represents a critical cellular signaling cascade involved in numerous biological processes including cell survival, proliferation, and metabolic regulation. This pathway activation subsequently enhanced the expression levels and enzymatic activity of CYP19A1, also known as aromatase, which is the key enzyme responsible for converting androgens to estrogens and plays a crucial role in maintaining appropriate hormonal balance in reproductive tissues.
The enhancement of CYP19A1 expression and enzymatic activity through SERPINE1 suppression facilitated more efficient androgen conversion processes in vitro, suggesting that SERPINE1 normally functions to suppress this conversion pathway and that its overexpression in response to circadian disruption contributes to androgen accumulation and hyperandrogenism development. These findings provide important mechanistic insights into how circadian disruption can lead to hormonal imbalances characteristic of polycystic ovary syndrome.
To validate the therapeutic potential of targeting SERPINE1 in polycystic ovary syndrome treatment, the research team conducted comprehensive in vivo studies using tiplaxtinin, a specific pharmacological inhibitor of SERPINE1 function. Treatment with tiplaxtinin demonstrated remarkable efficacy in alleviating both reproductive and metabolic abnormalities observed in experimental rat models of polycystic ovary syndrome. These therapeutic effects were observed in animals treated with dehydroepiandrosterone, a commonly used experimental model for inducing polycystic ovary syndrome-like conditions, as well as in animals exposed to continuous darkness conditions to model circadian disruption-induced hyperandrogenism.
The comprehensive findings presented in this investigation highlight the crucial and previously unrecognized role of SERPINE1 in mediating circadian disruption-induced hyperandrogenism and establish this protein as a potentially valuable methylome-based diagnostic biomarker for polycystic ovary syndrome. The identification of specific DNA methylation patterns associated with SERPINE1 dysregulation could provide clinicians with improved tools for early detection and monitoring of polycystic ovary syndrome development, particularly in patients with histories of circadian disruption exposure.
Furthermore, the demonstrated efficacy of pharmacological SERPINE1 inhibition in ameliorating polycystic ovary syndrome-related abnormalities suggests that this approach represents a promising and novel therapeutic strategy for treating hyperandrogenic forms of polycystic ovary syndrome. PAI-039 This therapeutic approach could be particularly valuable for patients who do not respond adequately to conventional treatments or who experience significant side effects from current therapeutic options.
Keywords
The key research areas and molecular concepts addressed in this comprehensive investigation encompass DNA methylation patterns and their role in gene regulation, circadian disruption exposure and its physiological consequences, hyperandrogenism as a pathological condition and its underlying mechanisms, polycystic ovary syndrome as a complex endocrine disorder, and SERPINE1 protein function and its therapeutic targeting potential in reproductive endocrinology.