Abstract

AIMS Histone deacetylation regulates mammalian follicular development via ovarian granulosa cells (GCs) autophagy, but the underlying mechanisms remain largely unknown. This study aimed to elucidate the epigenetic role of HDAC2 in GC autophagy and follicular development through ZFP42. MATERIALS AND METHODS HDAC2 knockdown combined with autophagy detection were performed to identify the effect of HDAC2 on autophagy and ZFP42 in GCs. Subsequently, chromatin accessibility assay and CRISPR/dCas9-P300 epigenetic editing were used to explore the molecular mechanism that HDAC2 regulates the expression of ZFP42. Finally, In vitro and in vivo methods were applied to evaluate the functional effects of ZFP42 on autophagy and follicular development. KEY FINDINGS Knockdown of HDAC2 Induces autophagy in GCs. ZFP42 protein level dynamically decreased during follicular development. Chromatin accessibility assay and CRISPR/dCas9-P300 editing revealed that HDAC2 dynamically altered H3K27ac occupancy at the promoter of ZFP42 to activating transcriptional activation of ZFP42. Functionally, ZFP42 protein interacted with the autophagic marker Beclin1 to modulate autophagy. Moreover, ZFP42 promoted GC autophagy and apoptosis to decrease serum estradiol (E2) levels and block follicular development in vivo. SIGNIFICANCE These results provided mechanistic insights into ovarian follicle development, and proposed ZFP42 as a potential therapeutic target for autophagy-related reproductive disorders.