Abstract
Zygotic chromatin undergoes extensive reprogramming immediately after fertilization. It is generally accepted that maternal factors control this process. However, little is known about the underlying mechanisms. Here we report that maternal RAD9A, a key protein in DNA damage response pathway, is involved in post-zygotic embryo development, via a mouse model with conditional depletion of Rad9a alleles in oocytes of primordial follicles. Post-zygotic losses originate from delayed zygotic chromatin decondensation after depletion of maternal RAD9A. Pronucleus formation and DNA replication of most mutant zygotes are therefore deferred, which subsequently trigger the G2/M checkpoint and arrest development of most mutant zygotes. Delayed zygotic chromatin decondensation could also lead to increased reabsorption of post-implantation mutant embryos. In addition, our data indicate that delayed zygotic chromatin decondensation may be attributed to deferred epigenetic modification of histone in paternal chromatin after fertilization, as fertilization and resumption of secondary meiosis in mutant oocytes were both normal. More interestingly, most mutant oocytes could not support development beyond one-cell stage after parthenogenetic activation. Therefore, RAD9A may also play an important role in maternal chromatin reprogramming. In summary, our data reveal an important role of RAD9A in zygotic chromatin reprogramming and female fertility.
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Acknowledgements
We are grateful to Shi-Wen Li, Li-Juan Wang, and Hua Qin for their technical assistance. We also thank Dr. Heng-Yu Fan for providing antibodies, Dr. Enkui Duan, Dr. Ying Zhang, Dr. Zhi-Ming Han, and Dr. Jing-Pian Peng for their useful suggestions. This study was supported by the National Key R& D Program of China (2016YFA0100400, 2016YFC1000600) and the National Natural Science Foundation of China (No. 31272260, 31371451, 31530049).
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L.H. and Q.-Y.S. conceived and designed the experiments. L.H., T.-G.M., X.-S.M., Z.-B.W., S.-T.Q., Q.C., Q.-H.Z., Q.-X.L., Z.-W.W., M.-W.H., L.G., and Y.-C.O. performed the experiments. L.H. analyzed the data. Y.H. contributed reagents, materials and analysis tools. Y.Z. provided the Rad9aF/F mouse strain. L.H. and Q.-Y.S. wrote the manuscript. All authors read and approved the final manuscript.
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Huang, L., Meng, TG., Ma, XS. et al. Rad9a is involved in chromatin decondensation and post-zygotic embryo development in mice. Cell Death Differ 26, 969–980 (2019). https://doi.org/10.1038/s41418-018-0181-9
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DOI: https://doi.org/10.1038/s41418-018-0181-9
