ZAR1/2‐Regulated Epigenetic Modifications are Essential for Age‐Associated Oocyte Quality Maintenance and Zygotic Activation
Abstract 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 f...
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202410305 |
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| author | Yan Rong Yu‐Ke Wu Yingyan Chen Qing Liu Leilei Ai Yun‐Wen Wu Yezhang Zhu Yin‐Li Zhang Chengkan Liu Yerong Ma Xiaomei Tong Jiamin Jin Xiaoxuan Li Yan Zhou Shu‐Yan Ji Songying Zhang Heng‐Yu Fan |
| author_facet | Yan Rong Yu‐Ke Wu Yingyan Chen Qing Liu Leilei Ai Yun‐Wen Wu Yezhang Zhu Yin‐Li Zhang Chengkan Liu Yerong Ma Xiaomei Tong Jiamin Jin Xiaoxuan Li Yan Zhou Shu‐Yan Ji Songying Zhang Heng‐Yu Fan |
| author_sort | Yan Rong |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-55966b2eb9c246aa8fa203251fca4380 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-55966b2eb9c246aa8fa203251fca43802025-08-20T01:51:48ZengWileyAdvanced Science2198-38442025-02-01128n/an/a10.1002/advs.202410305ZAR1/2‐Regulated Epigenetic Modifications are Essential for Age‐Associated Oocyte Quality Maintenance and Zygotic ActivationYan Rong0Yu‐Ke Wu1Yingyan Chen2Qing Liu3Leilei Ai4Yun‐Wen Wu5Yezhang Zhu6Yin‐Li Zhang7Chengkan Liu8Yerong Ma9Xiaomei Tong10Jiamin Jin11Xiaoxuan Li12Yan Zhou13Shu‐Yan Ji14Songying Zhang15Heng‐Yu Fan16Department of Obstetrics and Gynecology Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease Assisted Reproduction Unit Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 ChinaMOE Key Laboratory for Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute Zhejiang University Hangzhou 310058 ChinaDepartment of Obstetrics and Gynecology Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease Assisted Reproduction Unit Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 ChinaDepartment of Traditional Chinese Medicine Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou 310016 ChinaDepartment of Obstetrics and Gynecology Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease Assisted Reproduction Unit Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 ChinaMOE Key Laboratory for Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute Zhejiang University Hangzhou 310058 ChinaMOE Key Laboratory for Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute Zhejiang University Hangzhou 310058 ChinaDepartment of Obstetrics and Gynecology Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease Assisted Reproduction Unit Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 ChinaDepartment of Obstetrics and Gynecology Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease Assisted Reproduction Unit Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 ChinaDepartment of Obstetrics and Gynecology Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease Assisted Reproduction Unit Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 ChinaDepartment of Obstetrics and Gynecology Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease Assisted Reproduction Unit Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 ChinaDepartment of Obstetrics and Gynecology Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease Assisted Reproduction Unit Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 ChinaDepartment of Obstetrics and Gynecology Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease Assisted Reproduction Unit Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 ChinaDepartment of Obstetrics and Gynecology Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease Assisted Reproduction Unit Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 ChinaMOE Key Laboratory for Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute Zhejiang University Hangzhou 310058 ChinaDepartment of Obstetrics and Gynecology Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease Assisted Reproduction Unit Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 ChinaDepartment of Obstetrics and Gynecology Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease Assisted Reproduction Unit Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 ChinaAbstract 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.https://doi.org/10.1002/advs.202410305histone modificationsmaternal factoroocyte epigenetic maturationoocyte‐to‐embryo transitionreproductive aging |
| spellingShingle | Yan Rong Yu‐Ke Wu Yingyan Chen Qing Liu Leilei Ai Yun‐Wen Wu Yezhang Zhu Yin‐Li Zhang Chengkan Liu Yerong Ma Xiaomei Tong Jiamin Jin Xiaoxuan Li Yan Zhou Shu‐Yan Ji Songying Zhang Heng‐Yu Fan ZAR1/2‐Regulated Epigenetic Modifications are Essential for Age‐Associated Oocyte Quality Maintenance and Zygotic Activation Advanced Science histone modifications maternal factor oocyte epigenetic maturation oocyte‐to‐embryo transition reproductive aging |
| title | ZAR1/2‐Regulated Epigenetic Modifications are Essential for Age‐Associated Oocyte Quality Maintenance and Zygotic Activation |
| title_full | ZAR1/2‐Regulated Epigenetic Modifications are Essential for Age‐Associated Oocyte Quality Maintenance and Zygotic Activation |
| title_fullStr | ZAR1/2‐Regulated Epigenetic Modifications are Essential for Age‐Associated Oocyte Quality Maintenance and Zygotic Activation |
| title_full_unstemmed | ZAR1/2‐Regulated Epigenetic Modifications are Essential for Age‐Associated Oocyte Quality Maintenance and Zygotic Activation |
| title_short | ZAR1/2‐Regulated Epigenetic Modifications are Essential for Age‐Associated Oocyte Quality Maintenance and Zygotic Activation |
| title_sort | zar1 2 regulated epigenetic modifications are essential for age associated oocyte quality maintenance and zygotic activation |
| topic | histone modifications maternal factor oocyte epigenetic maturation oocyte‐to‐embryo transition reproductive aging |
| url | https://doi.org/10.1002/advs.202410305 |
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