Pathogenic mechanism of abnormal expression of HDAC3 in ovulatory granulosa cells inducing oocyte maturation disorder and its application in IVM.

Female reproductive health is troubled by oocyte maturation disorder. In mammals, granulosa cells (GCs) mediate luteinizing hormone (LH) action on oocyte maturation and ovulation. However, the pathogenesis of disordered GCs in oocyte maturation arrest is rarely studied. Our previous study has showed that HDAC3 (histone deacetylase 3) in GCs was decreased by LH at physiological conditions. Here, we observed significantly elevated HDAC3 levels in GCs from patients with oocyte maturation disorder following LH treatment compared with those with normal oocyte maturation. To clarify whether abnormally high levels of HDAC3 in ovulatory GCs resulted in female infertility, a mice model of GC-conditional overexpression of Hdac3 was constructed. The results showed that abnormally high levels of HDAC3 in ovulatory GCs inhibited LH induction on oocyte maturation and ovulation, resulting in female infertility. Further, in GCs with abnormal high levels of HDAC3, the upregulation of oocyte maturation-related genes induced by LH was attenuated by HDAC3 through a reduction in H3K14ac levels in the promoter regions, implying that the action of LH in GCs was largely negatively controlled by HDAC3. Applying HDAC3 inhibitors enhanced the expression of multiple genes associated with oocyte maturation in GCs from clinical patients, ultimately improving both the oocyte maturation rate and developmental quality, as demonstrated by a higher blastocyst development rate. The findings contribute to both enrich understanding upon the pathological mechanisms and supply optimal treatment strategies for patients with oocyte maturation disorder.