Granulosa cell mevalonate pathway abnormalities contribute to oocyte meiotic defects and aneuploidy [HiC GGOH-treatment]

The mechanisms of aging-related oocyte aneuploidy remain elusive. Hi-C and SMART-seq revealed aging-related decreases in chromosome condensation, particularly for genomic regions proximal to the centromeres, accompanied with disrupted meiosis-associated gene expression in metaphase I (MI) aged oocytes. Further transcriptomic analysis showed that oocyte meiotic maturation was correlated with robust increases in mevalonate (MVA) pathway gene expression in young oocyte-surrounding granulosa cells (GCs), which was largely downregulated in aged GCs. Inhibtion of MVA metabolism in GCs by statins resulted in marked meiotic defects and aneuploidy in young cumulus-oocyte complexes (COCs). Conversely, supplementation with the MVA isoprenoid geranylgeraniol ameliorated meiotic defects and aneuploidy in aged COCs. Meanwhile, geranylgeraniol also activated LHR/EGF signaling in aged GCs and then enhanced the meiosis-associated gene expression in oocytes. Generally, the MVA pathway in GCs is a critical regulator of meiotic maturation and euploidy in oocytes. Overall design: In this study, the dynamics of chromatin structure of oocytes and the overall transcriptomic landscape of oocytes and GCs throughout oocyte meiosis (growing phase, full-grown phase, metaphase I phase, metaphase II phase) in vivo from control or GGOH-treated aged mice were depicted.