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Previously we showed that HDAC inhibitor romidepsin potently inhibits axolotl tail regeneration when applied for only 1\u2010minute postamputation (MPA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here we tested CoCl<jats:sub>2,<\/jats:sub> a chemical that induces hypoxia and cellular stress, for potential to reverse romidepsin inhibition of tail regeneration. Partial rescue of regeneration was observed among embryos co\u2010treated with romidepsin and CoCl<jats:sub>2<\/jats:sub> for 1 MPA, however, extending the CoCl<jats:sub>2<\/jats:sub> dosage window either inhibited regeneration (CoCl<jats:sub>2<\/jats:sub>:0 to 30 MPA) or was lethal (CoCl<jats:sub>2<\/jats:sub>:0 to 24\u2009hours postamputation; HPA). CoCl<jats:sub>2<\/jats:sub>:0 to 30 MPA caused tissue damage, tissue loss, and cell death at the distal tail tip, while CoCl<jats:sub>2<\/jats:sub> treatment of non\u2010amputated embryos or CoCl<jats:sub>2<\/jats:sub>:60 to 90 MPA treatment after re\u2010epithelialization did not inhibit tail regeneration. CoCl<jats:sub>2<\/jats:sub>\u2010romidepsin:1 MPA treatment partially restored expression of transcription factors that are typical of appendage regeneration, while CoCl<jats:sub>2<\/jats:sub>:0 to 30 MPA significantly increased expression of genes associated with cell stress and inflammation. Additional experiments showed that CoCl<jats:sub>2<\/jats:sub>:0 to 1 MPA and CoCl<jats:sub>2<\/jats:sub>:0 to 30 MPA significantly increased levels of glutathione and reactive oxygen species, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study identifies a temporal window from tail amputation to re\u2010epithelialization, within which injury activated cells are highly sensitive to CoCl<jats:sub>2<\/jats:sub> perturbation of redox homeostasis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/dvdy.294","type":"journal-article","created":{"date-parts":[[2021,1,10]],"date-time":"2021-01-10T08:51:32Z","timestamp":1610268692000},"page":"852-865","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Chemical genetics of regeneration: Contrasting temporal effects of CoCl<sub>2<\/sub> on axolotl tail regeneration"],"prefix":"10.1002","volume":"250","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1496-2561","authenticated-orcid":false,"given":"Nour W. Al Haj","family":"Baddar","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Spinal Cord and Brain Injury Research Center, and Ambystoma Genetic Stock Center University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varun B.","family":"Dwaraka","sequence":"additional","affiliation":[{"name":"Department of Biology University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa V.","family":"Ponomareva","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Center for Pharmaceutical Research and Innovation University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon S.","family":"Thorson","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Center for Pharmaceutical Research and Innovation University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8332-3176","authenticated-orcid":false,"given":"S. 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