Article

Dynamic epigenomic landscapes during early lineage specification in mouse embryos

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Abstract

In mammals, all somatic development originates from lineage segregation in early embryos. However, the dynamics of transcriptomes and epigenomes acting in concert with initial cell fate commitment remains poorly characterized. Here we report a comprehensive investigation of transcriptomes and base-resolution methylomes for early lineages in peri- and postimplantation mouse embryos. We found allele-specific and lineage-specific de novo methylation at CG and CH sites that led to differential methylation between embryonic and extraembryonic lineages at promoters of lineage regulators, gene bodies, and DNA-methylation valleys. By using Hi-C experiments to define chromatin architecture across the same developmental period, we demonstrated that both global demethylation and remethylation in early development correlate with chromatin compartments. Dynamic local methylation was evident during gastrulation, which enabled the identification of putative regulatory elements. Finally, we found that de novo methylation patterning does not strictly require implantation. These data reveal dynamic transcriptomes, DNA methylomes, and 3D chromatin landscapes during the earliest stages of mammalian lineage specification.

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Acknowledgements

We are grateful to members of the Xie laboratory for helpful comments during preparation of the manuscript. We thank J. Na for critical reading of the manuscript. This work was supported by the National Key R&D Program of China (2016YFC0900301 to W. Xie; 2017YFC1001401 to L.L.), the National Basic Research Program of China (2015CB856201 to W. Xie), the National Natural Science Foundation of China (31422031 to W. Xie), the THU-PKU Center for Life Sciences (W. Xie), Beijing Advanced Innovation Center for Structural Biology (W. Xie), and the Biomedical Research Council of A*STAR (Agency for Science, Technology and Research), Singapore (F.X.). W. Xie is a Howard Hughes Medical Institute (HHMI) International Research Scholar. J.W. was funded by grants from the NIH (R01GM095942 and R21HD087722) and the Empire State Stem Cell Fund through the New York State Department of Health (NYSTEM) (C028103 and C028121), and is a recipient of an Irma T. Hirschl and Weill-Caulier Trusts Career Scientist Award.

Author information

Author notes

  1. Yu Zhang, Yunlong Xiang, Qiangzong Yin, and Zhenhai Du contributed equally to this work.

Affiliations

  1. Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China

    • Yu Zhang
    • , Yunlong Xiang
    • , Qiangzong Yin
    • , Zhenhai Du
    • , Qiujun Wang
    • , Weikun Xia
    • , Yuanyuan Li
    • , Wenhao Zhang
    • , Jing Ma
    •  & Wei Xie
  2. THU-PKU Center for Life Sciences, Tsinghua University, Beijing, China

    • Yunlong Xiang
    • , Zhenhai Du
    • , Qiujun Wang
    • , Weikun Xia
    • , Wenhao Zhang
    •  & Wei Xie
  3. Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore

    • Xu Peng
    •  & Feng Xu
  4. Department of Cell, Developmental and Regenerative Biology, and Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Miguel Fidalgo
    •  & Jianlong Wang
  5. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    • Zhen-ao Zhao
    •  & Lei Li
  6. Singapore Institute for Clinical Sciences, A*STAR, Singapore, Singapore

    • Feng Xu

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Contributions

Y.Z. and Q.Y. developed and conducted STEM-seq experiments. Y.X. dissected mouse tissues from embryos in vivo, carried out in vitro culture of embryos, and conducted RNA-seq. Z.D. conducted Hi-C experiments and related analysis. Z.Z. and L.L. advised on embryo lineage dissection. X.P. and F.X. advised on the development of STEM-seq. Y.L. and Q.W. conducted high-throughput sequencing. Y.Z. and Y.X. carried out data analysis. Q.W., W.Z., and W. Xia helped with the generation of Tet1/2 double-knockout mice. J.M., M.F., and J.W. helped with various experiments and/or advised the project. Y.Z. and W. Xie wrote the manuscript.

Competing interests

A patent for STEM-seq has been filed (2014104662612 China and PCT/CN2015/088680).

Corresponding author

Correspondence to Wei Xie.

Integrated Supplementary Information

Supplementary information

  1. Supplementary Figures

    Supplementary Figures 1–10.

  2. Life Sciences Reporting Summary

  3. Supplementary Table 1

    Lists of lineage-specific genes from E3.5 to E7.5.

  4. Supplementary Table 2

    Sequencing summary.

  5. Supplementary Table 3

    Differentially methylated genes.

  6. Supplementary Table 4

    Lists of all UMRs and LMRs.

  7. Supplementary Table 5

    Early-embryo-specific UMRs and LMRs.