Inhibition of HDAC4 in granulosa cells improves co-cultured porcine oocyte maturation in vitro independently of LH

ABSTRACT In domestic animals, the mechanisms by which the luteinizing hormone (LH) surge induces oocyte meiosis resumption and maturation through follicular somatic cells remain unclear. Given the pivotal roles of histone deacetylases in regulating gametogenesis, this study investigated the roles of histone deacetylases in follicular granulosa cells in mediating LH action during oocyte maturation in pigs. The results showed that histone deacetylase 4 (HDAC4) levels in cultured granulosa cells increased in a time-dependent manner with follicle-stimulating hormone stimulation but significantly decreased with LH treatment. The LH-induced reduction of HDAC4 was mediated by the accumulation of extracellular signal-regulated kinase 1/2 (ERK1/2), which subsequently increased H3K18 acetylation and promoted the recruitment of SMAD family member 3 (SMAD3) to the promoter of the EGF-like growth factor amphiregulin (AREG). Notably, specific inhibition of HDAC4 promoted oocyte maturation independently of LH in vitro, and the developmental potential of these matured oocytes was comparable to those induced by LH in vitro. In conclusion, HDAC4 in follicular somatic cells serves as a gonadotrophin-responsive epigenetic modification factor that negatively regulates oocyte meiosis resumption in pigs.