Localized epigenetic silencing of a damage-activated WNT enhancer limits regeneration in mature Drosophila imaginal discs
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 th...
| Main Authors: | , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
eLife Sciences Publications, Ltd.
2016
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| Online Access: | http://hdl.handle.net/1721.1/101717 https://orcid.org/0000-0003-4193-497X |
| _version_ | 1811069128853684224 |
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| author | Setiawan, Linda Saul, Joshua Clayton Harris, Robin E. Hariharan, Iswar K. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Setiawan, Linda Saul, Joshua Clayton Harris, Robin E. Hariharan, Iswar K. |
| author_sort | Setiawan, Linda |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T08:06:10Z |
| format | Article |
| id | mit-1721.1/101717 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:06:10Z |
| publishDate | 2016 |
| publisher | eLife Sciences Publications, Ltd. |
| record_format | dspace |
| spelling | mit-1721.1/1017172022-09-30T07:31:43Z Localized epigenetic silencing of a damage-activated WNT enhancer limits regeneration in mature Drosophila imaginal discs Setiawan, Linda Saul, Joshua Clayton Harris, Robin E. Hariharan, Iswar K. Massachusetts Institute of Technology. Department of Biology Saul, Joshua Clayton 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. 2016-03-16T16:10:13Z 2016-03-16T16:10:13Z 2016-02 2015-09 Article http://purl.org/eprint/type/JournalArticle 2050-084X http://hdl.handle.net/1721.1/101717 Harris, Robin E, Linda Setiawan, Josh Saul, and Iswar K Hariharan. “Localized Epigenetic Silencing of a Damage-Activated WNT Enhancer Limits Regeneration in matureDrosophilaimaginal Discs.” eLife 5 (February 3, 2016). https://orcid.org/0000-0003-4193-497X en_US http://dx.doi.org/10.7554/eLife.11588 eLife Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf eLife Sciences Publications, Ltd. eLife Sciences Publications, Ltd. |
| spellingShingle | Setiawan, Linda Saul, Joshua Clayton Harris, Robin E. Hariharan, Iswar K. Localized epigenetic silencing of a damage-activated WNT enhancer limits regeneration in mature Drosophila imaginal discs |
| title | Localized epigenetic silencing of a damage-activated WNT enhancer limits regeneration in mature Drosophila imaginal discs |
| title_full | Localized epigenetic silencing of a damage-activated WNT enhancer limits regeneration in mature Drosophila imaginal discs |
| title_fullStr | Localized epigenetic silencing of a damage-activated WNT enhancer limits regeneration in mature Drosophila imaginal discs |
| title_full_unstemmed | Localized epigenetic silencing of a damage-activated WNT enhancer limits regeneration in mature Drosophila imaginal discs |
| title_short | Localized epigenetic silencing of a damage-activated WNT enhancer limits regeneration in mature Drosophila imaginal discs |
| title_sort | localized epigenetic silencing of a damage activated wnt enhancer limits regeneration in mature drosophila imaginal discs |
| url | http://hdl.handle.net/1721.1/101717 https://orcid.org/0000-0003-4193-497X |
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