{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T02:11:18Z","timestamp":1789265478645,"version":"build-2803163510"},"reference-count":65,"publisher":"National Academy of Sciences","issue":"51","license":[{"start":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T00:00:00Z","timestamp":1734048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000055","name":"HHS | NIH | National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["R01DC020268"],"award-info":[{"award-number":["R01DC020268"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000055","name":"HHS | NIH | National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["F31 DC020633"],"award-info":[{"award-number":["F31 DC020633"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000055","name":"HHS | NIH | National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["T32 DC009975"],"award-info":[{"award-number":["T32 DC009975"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,12,17]]},"abstract":"<jats:p>\n                    During tissue regeneration, lineage-related cells can switch their fate to replace missing cells. This cell plasticity is particularly prominent in more regenerative vertebrates such as zebrafish, yet the molecular basis by which cells transdifferentiate into another cell type upon injury remains unclear. Here, we investigate the epigenetic basis of regenerative transdifferentiation in the inner ear, where supporting cells (SCs) generate mechanosensory hair cells (HCs) upon damage. By comparing the chromatin landscapes in regenerative zebrafish and green anole lizards versus nonregenerative mice, we identified a class of enhancers that function in progenitors to generate HCs and then are selectively maintained in SCs of regenerative vertebrates to regenerate HCs. In particular, we uncovered a syntenic class of long-range enhancers for\n                    <jats:italic>Atoh1<\/jats:italic>\n                    , a master transcription factor for HC differentiation. In the absence of injury, these enhancers maintain accessibility in SCs through adulthood but are prevented from driving zebrafish\n                    <jats:italic>atoh1a<\/jats:italic>\n                    expression through Notch repression. Deletion of these enhancers not only impaired\n                    <jats:italic>atoh1a<\/jats:italic>\n                    expression and HC formation during development but also blocked the ability of SCs to transdifferentiate into HCs during regeneration. Moreover, defects were specific to the inner ear versus the lateral line, revealing distinct mechanisms of regeneration in these mechanosensory organs. These findings reveal a class of regenerative enhancer that maintains competency of inner ear SCs to upregulate\n                    <jats:italic>atoh1a<\/jats:italic>\n                    and transdifferentiate into HCs upon damage. We propose that the continued accessibility of developmental enhancers for one cell fate in lineage-related cells may be a common theme underlying adult cell plasticity in regenerative vertebrates.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2418098121","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T11:18:21Z","timestamp":1734088701000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":10,"title":["Long-range\n                    <i>Atoh1<\/i>\n                    enhancers maintain competency for hair cell regeneration in the inner ear"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5268-0146","authenticated-orcid":false,"given":"Tuo","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California","place":["Los Angeles"]},{"name":"Caruso Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeeun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California","place":["Los Angeles"]},{"name":"Caruso Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Llamas","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California","place":["Los Angeles"]},{"name":"Caruso Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2384-7218","authenticated-orcid":false,"given":"Xizi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California","place":["Los Angeles"]},{"name":"Caruso Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Fabian","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6855-3571","authenticated-orcid":false,"given":"Thomas P.","family":"Lozito","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0441-2067","authenticated-orcid":false,"given":"Neil","family":"Segil","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California","place":["Los Angeles"]},{"name":"Caruso Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3870-9256","authenticated-orcid":false,"given":"Ksenia","family":"Gnedeva","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California","place":["Los Angeles"]},{"name":"Caruso Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3209-0026","authenticated-orcid":false,"given":"J. 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Shi Long-range Atoh1 enhancers maintain competency for hair cell regeneration in the inner ear. The National Center for Biotechnology Information Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE273764. Deposited 1 August 2024."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2418098121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T11:18:24Z","timestamp":1734088704000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2418098121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,13]]},"references-count":65,"journal-issue":{"issue":"51","published-print":{"date-parts":[[2024,12,17]]}},"alternative-id":["10.1073\/pnas.2418098121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2418098121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,13]]},"assertion":[{"value":"2024-09-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2418098121"}}