Serum and serum-derived extracellular vesicle microRNA signatures linked to neurodevelopmental processes in central precocious puberty
TL;DR
The coordinated alteration of freely circulating and EV-associated miRNAs highlight the potential contribution of miRNA-mediated regulation to premature HPG axis activation and provides a framework for further investigation of the molecular mechanisms underlying pubertal disorders.
Abstract
Background Central precocious puberty (CPP) results from premature activation of the hypothalamic–pituitary–gonadal (HPG) axis. While hormonal mechanisms underlying pubertal initiation are well established, the molecular regulatory processes accompanying altered pubertal timing remain incompletely understood. Circulating microRNAs (miRNAs), detectable either freely or within extracellular vesicles (EVs), represent a molecular layer of post-transcriptional regulation associated with pubertal development. Methods Serum samples from female patients diagnosed with CPP and age-matched healthy female controls were analyzed by small RNA sequencing to identify differentially expressed miRNAs. Selected miRNAs were validated by quantitative real-time PCR (RT–qPCR) in an expanded cohort using serum RNA and RNA isolated from serum-derived EVs. Functional enrichment analysis was conducted using experimentally validated miRNA target genes. Results Small RNA sequencing identified ten miRNAs with significantly altered expression levels in CPP (adjusted p-value < 0.05, |log2FC| > 0.5). Pathway enrichment analysis highlighted biological processes related to neurodevelopment, growth regulation and cellular maturation. RT–qPCR validation confirmed reduced serum expression of miR-125a-5p, miR-125b-5p and miR-99b-5p in CPP patients. All selected miRNAs were detectable in serum-derived EVs. Notably, miR-148a-3p exhibited a statistically significant increase specifically within the EV-associated fraction of CPP samples. Conclusions This study provides a comprehensive analysis of the circulating miRNA profile in female patients with CPP. The coordinated alteration of freely circulating and EV-associated miRNAs highlight the potential contribution of miRNA-mediated regulation to premature HPG axis activation and provides a framework for further investigation of the molecular mechanisms underlying pubertal disorders.