ZAR1/2-Regulated Epigenetic Modifications are Essential for Age-Associated Oocyte Quality Maintenance and Zygotic Activation.

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 partially redundant roles in maintaining oocyte quality, mainly known by regulating mRNA stability. In addition to this known function, it is found that ZAR1/2 is required for oocyte epigenetic maturation and zygotic reprogramming. Zar1/2-deleted oocytes exhibited reduced levels of multiple histone modifications and of the expression of corresponding histone modifiers, along with over-condensed chromatin, leading to compromised minor zygotic genome activation and deficient embryo development following fertilization. Cytoplasmic ZAR1/2 participated in intranuclear epigenetic maturation by binding the transcripts encoding histone modifiers and regulating their stability and translational activity. Moreover, oocytes from aged mice exhibited similar histone-modification deficiencies as the Zar1/2-deleted oocytes. ZAR1/2 mRNA and protein levels are downregulated in oocytes from mice and women with advanced ages, suggesting ZAR1/2 as regulators of epigenetic changes with reproductive aging. This study presents a new nucleo-cytoplasmic interaction mechanism that is involved in preventing oocyte epigenetic aging. Further, ZAR1/2 represents potential gene targets for diagnosis and clinical interventions in age-associated deficiencies in oocyte and embryo development.