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Parental noncoding RNAs choreograph pre and post fertilization events

ABSTRACT: The fusion of two terminally differentiated gametes, a sperm and an oocyte, results in the formation of a totipotent zygote, which is the first step in the development of a mammalian embryo. As the embryo progresses from pre- to post-implantation stage, significant structural and transcriptional changes take place within the embryonic lineage to ensure the success of a series of crucial biological events, such as oocyte activation and maternal-to-zygotic transition coordinated with zygotic gene activation, followed by the first cell-fate decision and lineage-specific differentiation, laying the foundation for the subsequent phase of gastrulation. LncRNAs are mostly transcribed by RNA polymerase II and are longer than 200 nts in length. They can interact with multiple molecules, including DNA, RNA, and protein, for regulating transcription, inducing epigenetic and translational modifications. miRNAs control the regulation of mRNAs by targeting it post transcriptionally. The importance of lncRNAs and miRNAs in germ cell development leads to successful fertilization and subsequently towards post fertilization events. The detail contribution of the maternal and paternal ncRNA profile towards fine tuning these events remain to be deciphered. All these motivated us to look into the parental ncRNA profile within mature fertile sperm and oocyte as well as zygote in mouse system, followed by an in-depth analysis to understand their modes of regulation which finetunes fertilization as well as post fertilization events prior to ZGA.

ORGANISM(S): Mus musculus

PROVIDER: GSE269614 | GEO | 2025/09/30

REPOSITORIES: GEO

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Project description:Background Fertilization involves interactions between sperm and metaphase II (MII) oocyte, initiating a cascade of events including oocyte activation, calcium release, resumption of meiosis, and zygote formation. Total fertilization failure (TFF), characterized by disruption of any of these processes, occurs in 1-3% of intracytoplasmic sperm injection (ICSI) cycles. The genetic basis of TFF remains largely unexplored. Methods We recruited a familial case of TFF. We assessed sperm parameters, binding ability, and fertilization outcomes using molecular assays and confocal microscopy. The whole genome sequencing and comprehensive genetic analyses were performed on the patients and family members to identify potential loss-of-function variants in genes involved in oogenesis and fertilization. Additionally, single-cell RNA sequencing of the patient's MII oocytes was conducted to assess transcriptomic profile. Two ICSI cycles were performed, one of which included assisted oocyte activation (AOA) using a calcium ionophore. Integrated bioinformatic analysis using RNA-seq and ATAC-seq was used to map genome-wide regulatory landscape in normal oocytes and early embryos. An enhancer-mediated gene regulatory network (eGRN) was constructed to assess the impact of mutations on transcription factor binding and gene regulation across the different GO BP and Reactome pathways. Results Despite normal sperm parameters in the husband and the absence of genetic variants related to oocyte activation in both partners, RNA-seq revealed aberrant expression of genes involved in meiosis, zona pellucida biogenesis, and oocyte activation. RNA-seq and ATAC-seq data identified 22 key transcription factors whose binding is significantly affected by the mutational landscape of the patient’s oocytes and that may disrupt downstream pathways involved in oogenesis, fertilization, and early embryonic development. ZNF121, TFAP2D, VEZF1 and YY1 were the top 4 hub TFs discovered in GO terms network. Additionally, TFAP2D, YY1, ZFP28 and ZNF121 were the most connected TFs to different Reactome pathways. Conclusions Our findings suggest that transcriptional dysregulations play a central role in total fertilization failure (TFF), by impacting downstream gene expression. Although, assisted oocyte activation with calcium ionophore helped successfully achieve fertilization, leading to the development of an 8-cell embryo. The insights from our study provide valuable opportunities for targeted interventions and potential therapeutic strategies in reproductive medicine.

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Parental noncoding RNAs choreograph pre and post fertilization events

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