ZAR1/2-regulated Histone Modifications are Required for Zygotic Activation and Age-associated Oocyte Quality Maintenance

The developmental competence and epigenetic progression of oocytes gradually become dysregulated with increasing maternal age. However, the mechanisms underlying age-related epigenetic regulation in oocytes remain poorly understood. Zygote arrest proteins 1 and 2 (ZAR1/2) are two maternal factors with redundant roles in maintaining oocyte quality. Here, we found that Zar1/2-deleted oocytes exhibited reduced levels of multiple histone modifications and of the corresponding histone modifiers, along with over-condensed chromatin, leading to disordered histone modification, compromised zygotic genome activation and deficient embryo development following fertilisation. Cytoplasmic ZAR1/2 participated in intranuclear epigenetic maturation by binding to the transcripts that encoding histone modifiers in oocytes, and regulating their stability and translational activity. Moreover, oocytes from older mice exhibited similar histone-modification deficiency to Zar1/2-deleted oocytes. In contrast, forced ZAR1/2 expression in aged mouse oocytes partially restored histone modifications. ZAR1/2 mRNA and protein levels were lower in oocytes from older mice and in those from older women, suggesting ZAR1/2 as regulators of aging-associated epigenetic disorganizations. This study presents a new nucleo-ooplasmic interaction mechanism that is vital for oocyte epigenetic maturation and declining of developmental potentials with female aging. Further, it provides the potential gene targets for diagnosis and clinical intervention in age-associated deficiency in oocyte and embryo development.