Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1

Yingfeng Li, Zhuqiang Zhang, Jiayu Chen, Wenqiang Liu, Weiyi Lai, Baodong Liu, Xiang Li, Liping Liu, Shaohua Xu, Qiang Dong, Mingzhu Wang, Xiaoya Duan, Jiajun Tan, Yong Zheng, Pumin Zhang, Guoping Fan, Jiemin Wong, Guoliang Xu, Zhigao Wang, Hailin WangShaorong Gao, Bing Zhu

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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 regions2–4. 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 fertility5–7, 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.

Original languageEnglish
Pages (from-to)136-140 (2018)
Number of pages5
JournalNature
Volume564
Issue number7734
Early online date28 Nov 2018
DOIs
Publication statusPublished - 6 Dec 2018

Keywords

  • Oocyte Genome
  • Major Satellite Repeats
  • Bisulfite Sanger Sequencing
  • Spindle-chromosome Complex
  • Media Assets

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    Li, Y., Zhang, Z., Chen, J., Liu, W., Lai, W., Liu, B., Li, X., Liu, L., Xu, S., Dong, Q., Wang, M., Duan, X., Tan, J., Zheng, Y., Zhang, P., Fan, G., Wong, J., Xu, G., Wang, Z., ... Zhu, B. (2018). Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1. Nature, 564(7734), 136-140 (2018). https://doi.org/10.1038/s41586-018-0751-5