Postnatal growth of mammalian oocytes is accompanied by a progressive gain of DNA methylation, which is predominantly mediated by DNMT3A, a de novo DNA methyltransferase1,2. Unlike the genome of sperm and most somatic cells, the oocyte genome is hypomethylated in transcriptionally inert regions2,3,4. However, how such a unique feature of the oocyte methylome is determined and its contribution to the developmental competence of the early embryo remains largely unknown. Here we demonstrate the importance of Stella, a factor essential for female fertility5,6,7, in shaping the oocyte methylome in mice. Oocytes that lack Stella acquire excessive DNA methylation at the genome-wide level, including in the promoters of inactive genes. Such aberrant hypermethylation is partially inherited by two-cell-stage embryos and impairs zygotic genome activation. Mechanistically, the loss of Stella leads to ectopic nuclear accumulation of the DNA methylation regulator UHRF18,9, which results in the mislocalization of maintenance DNA methyltransferase DNMT1 in the nucleus. Genetic analysis confirmed the primary role of UHRF1 and DNMT1 in generating the aberrant DNA methylome in Stella-deficient oocytes. Stella therefore safeguards the unique oocyte epigenome by preventing aberrant de novo DNA methylation mediated by DNMT1 and UHRF1.
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Sequencing data reported in this paper are summarized in Supplementary Tables 2, 3 and have been deposited in the Gene Expression Omnibus database under accession code GSE78149. Uncropped film scans for Extended Data Figs. 1a, 2a–d, g–i, 8b are presented in Supplementary Fig. 1. Source data for Figs. 1c, 2d, 3c, i and Extended Data Figs. 1c–e, 2e, f, k, 1, 6c, 7j, 8d are provided. All other data are available from the corresponding author on reasonable request.
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The Stella−/− mice were provided by the RIKEN BRC through the National Bio-Resource Project of the MEXT, Japan, and they were initially deposited by T. Nakamura and T. Nakano. We thank staff from the Laboratory Animal Research Center for technical assistance. We thank X. Wang, Z. Shen and H. Huang for discussion. This work was primarily supported by the China National Science Foundation (31521002), and was also supported by the Chinese Ministry of Science and Technology (2015CB856200, 2016YFA0100400 and 2017YFA0504200), the Chinese Academy of Sciences (XDB08010103, XDBP10 and QYZDY-SSW-SMC031), the China National Science Foundation (31425013, 31530037, 31730047, 31721003, 31871446 and31871448), the Shanghai Chenguang Program (16CG17) and the Shanghai Municipal Medical and Health Discipline Construction Projects (2017ZZ02015). Z.Z. is sponsored by the Youth Innovation Promotion Association (2017133) of the Chinese Academy of Sciences. G.F. is supported by the National Institutes of Health (R01DE025474).
Y.L., Z.Z. and B.Z. designed this study. Y.L. performed the majority of the experiments. Z.Z. performed the bioinformatics analysis. J.C. and W. Liu isolated pronuclei and performed the mouse embryo experiments. W. Lai and B.L. performed the UHPLC–MS/MS experiments. X.L., L.L., S.X., Q.D., M.W., X.D., J.T., Y.Z. and Z.W. assisted with the experiments. P.Z. and J.W. provided Uhrf1fl/fl mice, G.F. and G.-L.X. provided Dnmt3afl/fl and Dnmt1fl/fl mice, G.-L.X. provided antibodies against mouse DNMT3A and DNMT3B. H.W. supervised the UHPLC–MS/MS experiments. S.G. supervised the mouse embryo manipulations. Y.L., Z.Z. and B.Z. wrote the manuscript, and all authors read and commented on the manuscript.