lncRNA GCAT1 is involved in premature ovarian insufficiency by regulating p27 translation in GCs via competitive binding to PTBP1

Abstract

Dysfunction of granulosa cells (GCs) leading to follicle atresia has been extensively studied as a major cause of premature ovarian insufficiency (POI), but the regulatory role of long non-coding RNAs (lncRNAs) in this process is still poorly understood. Here, we show that the lncRNA <i>LINC02690</i> or <i>GCAT1</i> (granulosa cell-associated transcript 1) is downregulated in GCs from patients with biochemical POI (bPOI), and we show a significant correlation between downregulated <i>GCAT1</i> and serum levels of follicle-stimulating hormone and anti-Müllerian hormone. Downregulation of <i>GCAT1</i> inhibited G1/S cell cycle progression and thus inhibited the proliferation of GCs. Mechanistically, we show that <i>GCAT1</i> competes with cyclin-dependent kinase inhibitor 1B (<i>CDKN1B</i>) mRNA for polypyrimidine tract-binding protein 1 (PTBP1) binding, and thus decreased <i>GCAT1</i> might promote PTBP1 binding to <i>CDKN1B</i> mRNA and thereby initiate CDKN1B protein (p27) translation. Together, our results suggest that downregulation of <i>GCAT1</i> under conditions of bPOI inhibits the proliferation of GCs through PTBP1-dependent p27 regulation, thus suggesting a novel form of lncRNA-mediated epigenetic regulation of GC function that contributes to the pathogenesis of POI.