1. Cell Biology
  2. Stem Cells and Regenerative Medicine
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Localized epigenetic silencing of a damage-activated WNT enhancer limits regeneration in mature Drosophila imaginal discs

  1. Robin E Harris
  2. Linda Setiawan
  3. Josh Saul
  4. Iswar K Hariharan  Is a corresponding author
  1. University of California, Berkeley, United States
  2. Massachusetts Institute of Technology, United States
Research Article
  • Cited 59
  • Views 3,948
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Cite this article as: eLife 2016;5:e11588 doi: 10.7554/eLife.11588

Abstract

Many organisms lose the capacity to regenerate damaged tissues as they mature. Damaged Drosophila imaginal discs regenerate efficiently early in the third larval instar (L3) but progressively lose this ability. This correlates with reduced damage-responsive expression of multiple genes, including the WNT genes wingless (wg) and Wnt6. We demonstrate that damage-responsive expression of both genes requires a bipartite enhancer whose activity declines during L3. Within this enhancer, a damage-responsive module stays active throughout L3, while an adjacent silencing element nucleates increasing levels of epigenetic silencing restricted to this enhancer. Cas9-mediated deletion of the silencing element alleviates WNT repression, but is, in itself, insufficient to promote regeneration. However, directing Myc expression to the blastema overcomes repression of multiple genes, including wg, and restores cellular responses necessary for regeneration. Localized epigenetic silencing of damage-responsive enhancers can therefore restrict regenerative capacity in maturing organisms without compromising gene functions regulated by developmental signals.

Article and author information

Author details

  1. Robin E Harris

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Linda Setiawan

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Josh Saul

    Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Iswar K Hariharan

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    ikh@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Hugo J Bellen, Howard Hughes Medical Institute, Baylor College of Medicine, United States

Publication history

  1. Received: September 14, 2015
  2. Accepted: February 2, 2016
  3. Accepted Manuscript published: February 3, 2016 (version 1)
  4. Version of Record published: February 26, 2016 (version 2)

Copyright

© 2016, Harris et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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