Mechanisms of Oocyte Maturation and Related Epigenetic Regulation

Abstract

Meiosis is the basis of sexual reproduction. In female mammals, meiosis of oocytes starts before birth and sustains at the dictyate stage of meiotic prophase I before gonadotropins-induced ovulation happens. Once meiosis gets started, the oocytes undergo the leptotene, zygotene, and pachytene stages, and then arrest at the dictyate stage. During each estrus cycle in mammals, or menstrual cycle in humans, a small portion of oocytes within preovulatory follicles may resume meiosis. It is crucial for females to supply high quality mature oocytes for sustaining fertility, which is generally achieved by fine-tuning oocyte meiotic arrest and resumption progression. Anything that disturbs the process may result in failure of oogenesis and seriously affect both the fertility and the health of females. Therefore, uncovering the regulatory network of oocyte meiosis progression illuminates not only how the foundations of mammalian reproduction are laid, but how mis-regulation of these steps result in infertility. In order to provide an overview of the recently uncovered cellular and molecular mechanism during oocyte maturation, especially epigenetic modification, the progress of the regulatory network of oocyte meiosis progression including meiosis arrest and meiosis resumption induced by gonadotropins is summarized. Then, advances in the epigenetic aspects, such as histone acetylation, phosphorylation, methylation, glycosylation, ubiquitination, and SUMOylation related to the quality of oocyte maturation are reviewed.

Keywords: meiosis arrest; meiosis resumption; oocyte; oocyte maturation; ovary.

FIGURE 1

Schematic model depicting the mechanisms of meiotic arrest. Meiotic arrest in fully grown oocytes is required by the synthesis and maintenance of high levels of cAMP, the arrest state is maintained by the cooperation of granulosa cells and oocytes in the follicles. In mural granulosa cells, FSH binds its receptor (FSHR), collaborating with androgen/AR, estrogen/ER, and the TGF-β/TGFBR2 signal pathway to promote NPPC transcription and increase NPPC production. In cumulus granulosa cells, FSH binds FSHR, collaborating with androgen/AR and estrogen/ER to promote NPR2 transcription and increase NPR2 production. NPPC actives NPR2, GTP is converted into cGMP, then cGMP enters the oocyte through CX37 gap junctions. In oocytes, cGMP inhibits PDE3A activity, prevents the degradation of cAMP, cAMP activates protein kinase A (PKA) that in turn activates the WEE1B kinase and inhibits the CDC25B phosphatase leading to the inactivation of CDK1. In addition, CDC25B protein level is inhibited by histone lysine demethylases 1A (KDM1A). The constant degradation of cyclin B1/2 (cycB1/2) by APC/CDH1 prevents MPF activation in the arrested oocytes.

FIGURE 2

Schematic model depicting the mechanisms of LH-induced meiotic resumption. A preovulatory surge of LH binds its receptor (LHR) and induces a series of events in granulosa cells. In mural granulosa cells, on the one hand, LH/LHR inhibits AR and ER to reduce NPPC transcription and decrease NPPC production, on the other hand, it induces the degradation of histone deacetylase 3 (HDAC3) to decrease the Ac-H3K14 level which enables transcription factor SP1 binding to the AREG promoter to initiate AREG transcription, then increases the EGF level. The production of EGFs activates EGFR signaling and elevates the level of calcium in cumulus granulosa cells to further inactivate NPR2. LH-LHR also causes closure of gap junctions in the follicle and prevents cGMP delivery to oocytes. This in turn increases cAMP degradation by PDE3A. Low levels of cAMP and PKA can no longer activate WEE1B and inactivate CDC25B, and CDK1 becomes dephosphorylated and catalytically active. In addition, activated CDK1 triggers CXXC-finger protein 1 (CXXC1, also known as CFP1) phosphorylation and degradation following the meiotic resumption. The degradation of CFP1 ensures the absence of the SET domain containing 1 (SETD1)-CXXC1 complex from the chromatin, thereby facilitating chromosome condensation during oocyte maturation.