1. Developmental Biology
  2. Stem Cells and Regenerative Medicine

Damage-responsive, maturity-silenced enhancers regulate multiple genes that direct regeneration in Drosophila

  1. Robin E Harris  Is a corresponding author
  2. Michael J Stinchfield
  3. Spencer L Nystrom
  4. Daniel J McKay
  5. Iswar K Hariharan  Is a corresponding author
  1. Arizona State University, United States
  2. University of North Carolina at Chapel Hill, United States
  3. University of California, Berkeley, United States
https://doi.org/10.7554/eLife.58305
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  1. Robin E Harris
  2. Michael J Stinchfield
  3. Spencer L Nystrom
  4. Daniel J McKay
  5. Iswar K Hariharan
(2020)
Damage-responsive, maturity-silenced enhancers regulate multiple genes that direct regeneration in Drosophila
eLife 9:e58305.
https://doi.org/10.7554/eLife.58305
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Abstract

Like tissues of many organisms, Drosophila imaginal discs lose the ability to regenerate as they mature. This loss of regenerative capacity coincides with reduced damage-responsive expression of multiple genes needed for regeneration. We previously showed that two such genes, wg and Wnt6, are regulated by a single damage-responsive enhancer that becomes progressively inactivated via Polycomb-mediated silencing as discs mature (Harris et al., 2016). Here we explore the generality of this mechanism and identify additional damage-responsive, maturity-silenced (DRMS) enhancers, some near genes known to be required for regeneration such as Mmp1, and others near genes that we now show function in regeneration. Using a novel GAL4-independent ablation system we characterize two DRMS-associated genes, apontic (apt), which curtails regeneration and CG9752/asperous (aspr), which promotes it. This mechanism of suppressing regeneration by silencing damage-responsive enhancers at multiple loci can be partially overcome by reducing activity of the chromatin regulator extra sex combs (esc).

Data availability

Sequencing data have been deposited in GEO. Accession code: GSE140755. All other data generated or analyzed during this study are included in the manuscript and supporting files.

The following data sets were generated

Article and author information

Author details

  1. Robin E Harris

    School of Life Sciences, Arizona State University, Tempe, United States
    For correspondence
    Robin.Harris@asu.edu
    Competing interests
    The authors declare that no competing interests exist.

  2. Michael J Stinchfield

    School of Life Sciences, Arizona State University, Tempe, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Spencer L Nystrom

    Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1000-1579

  4. Daniel J McKay

    Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6505-0744

Funding

National Institutes of Health (R35 GM122490)

  • Iswar K Hariharan

American Cancer Society (RP-16238-06-COUN)

  • Iswar K Hariharan

National Institutes of Health (R35 GM128851)

  • Daniel J McKay

American Cancer Society (RSG-17-164-01-DDC)

  • Daniel J McKay

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2020, 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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  1. Robin E Harris
  2. Michael J Stinchfield
  3. Spencer L Nystrom
  4. Daniel J McKay
  5. Iswar K Hariharan
(2020)
Damage-responsive, maturity-silenced enhancers regulate multiple genes that direct regeneration in Drosophila
eLife 9:e58305.
https://doi.org/10.7554/eLife.58305

Share this article

https://doi.org/10.7554/eLife.58305

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Further reading

    1. Cell Biology
    2. Stem Cells and Regenerative Medicine

    Localized epigenetic silencing of a damage-activated WNT enhancer limits regeneration in mature Drosophila imaginal discs

    Robin E Harris, Linda Setiawan ... Iswar K Hariharan
    Research Article Updated

    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.