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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE212860 | GEO | 2023/02/26

REPOSITORIES: GEO

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Granulosa cell mevalonate pathway abnormalities contribute to oocyte meiotic defects and aneuploidy [RNA-seq mouse oocyte]

Project description:The mechanisms of oocyte meiotic defects and low competence during ovarian aging remains elusive for decades. Using Hi-C (genome-wide chromatin conformation capture) and Smart RNA-seq of oocytes from 6- weeks or 10- months aged ovaries, the abnormal loose chromatin structures and disturbing expression of meiosis associated genes at metaphase I phase were disclosed. Furthermore, the transcriptomic landscape of granulosa cells (GCs) surrounding oocytes from young and aged ovaries reveled that oocyte meiotic maturation was accompanied with a robust increased expression of genes involved with the mevalonate (MVA) pathway in GCs from young ovaries but these genes expression was not upregulated to counterpart level in GCs from aged ovaries.The inhibitor of MVA pathway of GCs, Statins significantly decreased polar body extrusion rate and increased the rate of irregularly assembled spindles and misaligned chromosomes remarkably in oocytes of culumus-oocyte complex (COCs) from young ovaries . Correspondingly, the activitor of MVA pathway of GCs, Geranylgeraniol ameliorated ovarian reserve and reduced meiotic defects in oocytes of COCs from aged ovaries. Mechanistically, MVA pathway activation in GCs culminated oocyte meiotic maturation by upregulating EGF signaling via LH receptor on GCs surrounding oocytes. Together, MVA pathway is a promising therapeutic target for prompting quality of oocytes from aged ovaries.

2023-02-26 | GSE175835 | GEO

Granulosa cell mevalonate pathway abnormalities contribute to oocyte meiotic defects and aneuploidy [RNA-seq mouse GC]

2023-02-26 | GSE175834 | GEO

Granulosa cell mevalonate pathway abnormalities contribute to oocyte meiotic defects and aneuploidy [RNA-seq Human oocytes]

2023-02-26 | GSE175833 | GEO

Granulosa cell mevalonate pathway abnormalities contribute to oocyte meiotic defects and aneuploidy [RNA-seq Human Granulosa cells]

2023-02-26 | GSE175832 | GEO

Granulosa cell mevalonate pathway abnormalities contribute to oocyte meiotic defects and aneuploidy [Hi-C]

2023-02-26 | GSE175830 | GEO

Growth hormone supplementation reduces aneuploidy and improves the quality of oocytes by activating ERK1/2 pathway in aged mice

Project description:The decline in oocyte quality is a limiting factor of female fertility; however, strategies to maintain the oocyte quality of aged women are not available. In this study, we showed that growth hormone (GH) supplementation in vivo not only alleviated the decline in oocyte number caused by aging, but also improved the quality and developmental potential of aged oocytes. Strikingly, GH supplementation reduced aneuploidy in aged oocytes. Proteomic analysis indicated that the ERK1/2 pathway was involved in the reduction in aneuploidy rate of aged oocytes, as confirmed both in vivo and in vitro. In addition, JAK2 might be involved in the regulation of ERK1/2 by GH in aged oocytes. Collectively, our findings revealed that GH supplementation protects oocytes from aging-related aneuploidy and enhances the quality of aged oocytes, and could be used to improve the outcome of assisted reproduction in aged women.

2023-07-20 | PXD039147 | Pride

Genome-wide mapping of crossovers in all products of adult, single human female meioses reveals structural rearrangements of chromosomes and meiotic drive for recombinant chromatids

Project description:Meiotic recombination promotes genomic diversity by generating new combinations of alleles, while at the same time, maintaining genome stability by preventing chromosome missegregation and aneuploidy, such as Down Syndrome. We report here the first genome-wide maps of meiotic recombination in the human female meiosis. By utilizing information from all three meiotic products (oocyte, polar body 1 and polar body 2), our data reveal crossover rates that are in great excess (~40%) of recombination rate estimates from population-based studies. Recovery of all three meiotic products allowed us to identify structural defects to meiotic chromosomes that originate during meiosis, as well as true meiotic drive at meiosis II for the preferential exclusion of non-recombinant chromatids from the oocyte. Finally, we identify a novel chromosome segregation pattern reminiscent of 'inverted meiosis' that leads to chromosomally-balanced oocytes. The three products of meiosis from 13 oocytes and the gDNA from the five donors were analysed (total of 44 samples). Blank (negative) and positive (genomic DNA) control samples were provided for each DNA amplifiction run. No replicates were included as they were not available. No external references were included.

2015-03-01 | E-GEOD-53539 | biostudies-arrayexpress

BCL-2 pathway counteracts aneuploidy in mammalian embryos

Project description:DNA double-strand breaks (DSBs) are toxic to mammalian cells. However, during meiosis, more than 200 DSBs are generated deliberately, to ensure reciprocal recombination and orderly segregation of homologous chromosomes. If left unrepaired, meiotic DSBs can cause aneuploidy in gametes and compromise viability in offspring. Oocytes in which DSBs persist are therefore eliminated by the DNA-damage checkpoint. The checkpoint’s downstream effectors that trigger oocyte death, thereby preserving genome stability across the generations, are unknown. Here we show that the DNA-damage checkpoint eliminates oocytes via the pro-apoptotic BCL-2 pathway members Puma, Noxa and Bax. Deletion of these factors prevents oocyte elimination in recombination-repair mutants, even when the abundance of unresolved DSBs is high. Remarkably, surviving oocytes can extrude a polar body and be fertilised, despite chaotic chromosome segregation at the first meiotic division. Our findings raise the possibility that allelic variants of the BCL-2 pathway could influence the risk of embryonic aneuploidy.

2020-03-26 | E-MTAB-8752 | biostudies-arrayexpress

The E2 SUMO-conjugating enzyme UBE2I is essential for chromatin dynamics and transcriptional silencing in mouse oocytes

Project description:In mammals, meiotically competent oocytes develop cyclically during ovarian folliculogenesis. During their development, prophase I arrested oocytes are highly transcriptionally active in preparation for the resumption of meiosis and early stages of embryogenesis prior to the maternal to zygotic transition. Defective oocyte development during folliculogenesis leads to meiotic defects, aneuploidy, follicular atresia, or non-viable embryos. SUMOylation, a dynamic post-translational protein modification, is essential for oocyte development during folliculogenesis and to regulate meiotic maturation in mice. We generated a novel oocyte-specific knockout of Ube2i, the sole SUMO E2 ligase, to test its role growing ovarian follicles using Zp3-cre. Ube2i Zp3-cre+ female mice are sterile with oocytes with defects in meiotic progression but not meiotic resumption. Importantly, fully grown oocytes do not silence transcription and prematurely activate the zygotic transcriptional program. This work uncovers unknown functions of UBE2i as a key orchestrator of chromatin and transcriptional regulation in oocytes.

2023-08-23 | GSE218484 | GEO

The chromatin remodeler Snf2h is essential for oocyte meiotic cell cycle progression

Project description:Oocytes are indispensable for mammalian life. Thus, it is important to understand how mature oocytes are generated. As a critical stage of oocytes development, meiosis has been extensively studied, yet how chromatin remodeling contributes to this process is largely unknown. Here, we demonstrate that the ATP-dependent chromatin remodeling factor Snf2h (also known as Smarca5) plays a critical role in regulating meiotic cell cycle progression. Females with oocyte-specific depletion of Snf2h are infertile and oocytes lacking Snf2h fail to undergo meiotic resumption. Mechanistically, depletion of Snf2h results in dysregulation of meiosis-related genes, which causes failure of maturation-promoting factor (MPF) activation. ATAC-seq analysis in oocytes revealed that Snf2h regulates transcription of a key meiotic gene, Prkar2b, by increasing its promoter chromatin accessibility. Our studies thus not only demonstrate the importance of Snf2h in oocyte meiotic resumption, but also reveal the mechanism underlying how a chromatin remodeling factor can regulate oocyte meiosis.

2020-01-19 | GSE134279 | GEO

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