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A multistep epigenetic switch enables the stable inheritance of DNA methylation states

Nature Genetics volume 39, pages 269275 (2007) | Download Citation

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Abstract

In many prokaryotes and eukaryotes, DNA methylation at cis-regulatory sequences determines whether gene expression is on or off. Stable inheritance of these expression states is required in bacterial pathogenesis, cancer and developmental pathways1,2. Here we delineate the factors that control the stability of these states by using the agn43 gene in Escherichia coli as a model system. Systematic disruption of this system shows that a functional switch requires the presence of several, rarely occupied, intermediate states that separate the 'on' and 'off' states. Cells that leave the on and off state enter different intermediate states, where there is a strong bias that drives cells back to their original state. The intermediate states therefore act as buffers that prevent back and forth switching. This mechanism of generating multiple states is an alternative to feedback regulation3,4,5, and its general principle should be applicable to the analysis of other epigenetic switches and the design of synthetic circuits.

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Acknowledgements

We thank E.A. Oakenfull for logistical assistance; M. Thattai for discussions and assistance with data analysis; M. van der Woude for bacterial strains and plasmids; R. Lutz and H. Bujard for pZ expression plasmids; and A. Becskei, S.V. Godoy and J.M. Pedraza for suggestions and comments. This work was supported by grants from the National Science Foundation (PHY-0548484) and the National Institutes of Health (R01-GM077183).

Author information

Affiliations

  1. Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

    • Han N Lim
    •  & Alexander van Oudenaarden
  2. Department of Integrative Biology, University of California, Berkeley, California 94720, USA.

    • Han N Lim

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Han N Lim.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Cis-regulatory deletion strains.

  2. 2.

    Supplementary Table 1

    Bacterial strains and plasmids.

  3. 3.

    Supplementary Table 2

    Oligonucleotide sequences.

  4. 4.

    Supplementary Methods

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DOI

https://doi.org/10.1038/ng1956

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