Hypomethylation‐Triggered SERPINE1 (Serpin Family E Member 1) Exacerbates Polycystic Ovary Syndrome with Hyperandrogenism Induced by Circadian Disruption

TL;DR

This study shows that reduced DNA methylation of SERPINE1, triggered by disrupted circadian rhythms, leads to increased androgen levels in a rat model of PCOS, and that inhibiting SERPINE1 can reduce these effects.

Contribution

The study identifies SERPINE1 as a novel hypomethylated gene linked to hyperandrogenism in PCOS and demonstrates its potential as a therapeutic target.

Findings

SERPINE1 is hypomethylated and upregulated in rats exposed to continuous darkness, correlating with elevated androgen levels.

SERPINE1 inhibition with tiplaxtinin reduces reproductive and metabolic abnormalities in PCOS rat models.

SERPINE1 suppression activates the PI3K/AKT pathway, enhancing androgen conversion via CYP19A1.

Abstract

Polycystic ovary syndrome (PCOS), a prevalent cause of female infertility, arises from complex interactions between genetic and environmental factors, with hyperandrogenism serving as a core pathological feature. While growing evidence links circadian disruptions to the development of hyperandrogenism in PCOS, the underlying mechanism remains unclear. In this study, we employed DNA methylation profiling and RNA sequencing of ovarian granulosa cells from rats exposed to 8‐week darkness, and identified serpin family E member 1 (SERPINE1) as a key player. SERPINE1 was significantly hypomethylated and upregulated in the dark group, correlating with elevated androgen levels. Mechanistically, using CRISPR–dCas9‐based targeted methylation, we found that CpG hypomethylation near the SERPINE1 transcription start site drove its overexpression. Functional assays revealed that SERPINE1 suppression activated the PI3K/AKT signaling pathway, thereby enhancing CYP19A1 expression and enzymatic activity to facilitate androgen conversion in vitro. Moreover, treatment with the SERPINE1 inhibitor tiplaxtinin alleviated both reproductive and metabolic abnormalities in rat models treated with either dehydroepiandrosterone or exposed to darkness. These findings highlight SERPINE1's role in circadian disruption‐induced hyperandrogenism and its potential as a methylome‐based diagnostic biomarker for PCOS. Pharmacological inhibition of SERPINE1 emerges as a promising therapeutic strategy for hyperandrogenic PCOS.

SERPINE1 shows CpG hypomethylation near its TSS of promoter region when exposed to circadian disruption, and its gene expression triggers hyperandrogenism through the PI3K/AKT pathway. SERPINE1 inhibitor TPX can significantly decrease serum SERPINE1 levels and reduce abnormally high testosterone levels in both continuous darkness‐exposed rats and DHEA‐treated rats.

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