| Summary: | Abnormal sexual maturity exhibits significant detrimental effects on adult health outcomes, and previous studies have indicated that targeting histone acetylation might serve as a potential therapeutic approach to regulate sexual maturity. However, the mechanisms that account for it remain to be further elucidated. Using the mouse model, we showed that Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, downregulated the protein level of Hdac1 in ovaries to promote the apoptosis of granulosa cells (GCs), and thus arrested follicular development and delayed sexual maturity. Using porcine GCs as a cell model, a novel sexual maturity-associated lncRNA, which was named as the stimulatory factor of follicular development (<i>SFFD</i>), transcribed from mitochondrion and mediated by <i>HDAC1</i>, was identified using RNA sequencing. Mechanistically, <i>HDAC1</i> knockdown significantly reduced the H3K27ac level at the −953/−661 region of <i>SFFD</i> to epigenetically inhibit its transcription. <i>SFFD</i> knockdown released miR-202-3p to reduce the expression of cyclooxygenase 1 (<i>COX1</i>), an essential rate-limited enzyme involved in prostaglandin synthesis. This reduction inhibited the proliferation and secretion of 17β-estradiol (E2) while promoting the apoptosis of GCs. Consequently, follicular development was arrested and sexual maturity was delayed. Taken together, <i>HDAC1</i> knockdown-mediated <i>SFFD</i> downregulation promoted the apoptosis of GCs through the miR-202-3p-<i>COX1</i> axis and lead to delayed sexual maturity. Our findings reveal a novel regulatory network modulated by <i>HDAC1</i>, and <i>HDAC1</i>-mediated <i>SFFD</i> may be a promising new therapeutic target to treat delayed sexual maturity.
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