Letter | Published:

Dynamic and static maintenance of epigenetic memory in pluripotent and somatic cells

Nature volume 513, pages 115119 (04 September 2014) | Download Citation


Stable maintenance of gene regulatory programs is essential for normal function in multicellular organisms. Epigenetic mechanisms, and DNA methylation in particular, are hypothesized to facilitate such maintenance by creating cellular memory1,2,3,4 that can be written during embryonic development5,6 and then guide cell-type-specific gene expression7. Here we develop new methods for quantitative inference of DNA methylation turnover rates, and show that human embryonic stem cells preserve their epigenetic state by balancing antagonistic processes that add and remove methylation marks rather than by copying epigenetic information from mother to daughter cells. In contrast, somatic cells transmit considerable epigenetic information to progenies. Paradoxically, the persistence of the somatic epigenome makes it more vulnerable to noise, since random epimutations can accumulate to massively perturb the epigenomic ground state. The rate of epigenetic perturbation depends on the genomic context, and, in particular, DNA methylation loss is coupled to late DNA replication dynamics. Epigenetic perturbation is not observed in the pluripotent state, because the rapid turnover-based equilibrium continuously reinforces the canonical state. This dynamic epigenetic equilibrium also explains how the epigenome can be reprogrammed quickly8 and to near perfection9 after induced pluripotency.

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Gene Expression Omnibus

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Raw data have been deposited in the Gene Expression Omnibus under accession number GSE53610.


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We thank E. Kenigsberg, E. Yaffe and the Tanay group for discussions. Research in the Tanay group was supported by the European Research Council (EVOEPIC), the EU BLUEPRINT project, the Israel Science Foundation (1050/12 and I-Core) the Israel Ministry of Science and the Helen and Martin Kimmel Award.

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Author notes

    • Zohar Shipony
    •  & Zohar Mukamel

    These authors contributed equally to this work.


  1. Department of Computer Science and Applied Mathematics, and Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel

    • Zohar Shipony
    • , Zohar Mukamel
    • , Netta Mendelson Cohen
    • , Gilad Landan
    • , Elad Chomsky
    •  & Amos Tanay
  2. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel

    • Elad Chomsky
  3. Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel

    • Shlomit Reich Zeliger
    •  & Nir Friedman
  4. Department of Biological Services, Weizmann Institute of Science, Rehovot 76100, Israel

    • Yael Chagit Fried
    •  & Elena Ainbinder


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Z.S., Z.M. and A.T. designed the study. Z.S. and Z.M. performed the experiments. Z.S., N.M.C. and A.T. developed the algorithms. Z.S., Z.M. and A.T. analysed the data. G.L. and E.C. helped in developing the experimental protocol and analytical framework. Y.C.F. and E.A. generated ES-cell clones. S.R.Z. and N.F. generated CD8+ T-cell clones. Z.S., Z.M. and A.T. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Amos Tanay.

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