{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:59:50Z","timestamp":1781110790805,"version":"3.54.1"},"reference-count":57,"publisher":"National Academy of Sciences","issue":"12","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,3,24]]},"abstract":"<jats:p>\n                    Organ development and function are orchestrated by intricate transcriptional circuits. Here, we present a comprehensive atlas profiling 1,904 transcription regulators in the brain, cerebellum, heart, kidney, liver, ovary, and testis of fetal, neonatal, and adult mice. Using this dataset, we uncover Thymocyte Selection-Associated High Mobility Group Box Family Member 3 (TOX3) as a potential coactivator of Atoh1 in cerebellar granule neuron progenitors (GNPs).\n                    <jats:italic toggle=\"yes\">Tox3<\/jats:italic>\n                    -deficient mice display severe ataxia and cerebellar hypoplasia, driven by depletion of GNPs, diminished\n                    <jats:italic toggle=\"yes\">Atoh1<\/jats:italic>\n                    expression, and impaired primary cilia. Single-nucleus RNA-sequencing analyses reveals compromised maintenance of the progenitor pool.\n                    <jats:italic toggle=\"yes\">TOX3<\/jats:italic>\n                    is also highly expressed in subsets of medulloblastoma, and its deletion reduces cerebellar neoplasia and prolongs survival in a mouse model. Mechanistically, how lineage-defining factors such as Atoh1 drive robust gene expression despite weak intrinsic transactivation activity remains unclear. We show that Tox3 physically associates with Atoh1 and co-occupies shared regulatory elements, converting an otherwise weak single-copy Atoh1-responsive E-box into a highly active enhancer that drives transcriptional activation by up to 120-fold, including at an ultraconserved E-box downstream of\n                    <jats:italic toggle=\"yes\">Atoh1<\/jats:italic>\n                    itself. Cross-species single-cell comparisons further show an association between\n                    <jats:italic toggle=\"yes\">Tox3<\/jats:italic>\n                    expression and cerebellum expansion during vertebrate evolution. Together, this work supports Tox3 as a critical Atoh1 coactivator in cerebellar development, tumorigenesis, and evolution, while providing an atlas and screening strategy as a valuable resource for exploring novel transcriptional regulators in organogenesis and tissue physiology.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2527163123","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T17:40:47Z","timestamp":1773855647000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["A transcription regulator atlas identifies TOX3 as an Atoh1 coactivator in cerebellar development and tumorigenesis"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3092-7010","authenticated-orcid":false,"given":"Xiaoxin","family":"Chen","sequence":"first","affiliation":[{"name":"Cardiovascular Research Institute, University of California San Francisco","place":["San Francisco"]},{"name":"Department of Physiology, University of California San Francisco","place":["San Francisco"]},{"name":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochen","family":"Zhong","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, University of California San Francisco","place":["San Francisco"]},{"name":"Department of Physiology, University of California San Francisco","place":["San Francisco"]},{"name":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Medicine and Division of Gastroenterology, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine and Division of Gastroenterology, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Woo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9648-8949","authenticated-orcid":false,"given":"Hani","family":"Goodarzi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaili","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Alabama at Birmingham","place":["Birmingham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6846-9014","authenticated-orcid":false,"given":"Q. Richard","family":"Lu","sequence":"additional","affiliation":[{"name":"Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children\u2019s Hospital Medical Center","place":["Cincinnati"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3360-2345","authenticated-orcid":false,"given":"Fr\u00e9d\u00e9ric","family":"Flamant","sequence":"additional","affiliation":[{"name":"Ecole Normale Sup\u00e9rieure de Lyon, Institut National de Recherche pour l\u2019Agriculture, l\u2019Alimentation et l\u2019Environnement (INRAE), CNRS, Institut de G\u00e9nomique Fonctionnelle de Lyon","place":["Lyon, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy F.","family":"Reiter","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of California San Francisco","place":["San Francisco"]},{"name":"Chan Zuckerberg Biohub","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4335-9123","authenticated-orcid":false,"given":"Guo N.","family":"Huang","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, University of California San Francisco","place":["San Francisco"]},{"name":"Department of Physiology, University of California San Francisco","place":["San Francisco"]},{"name":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco","place":["San 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nouvelles id\u00e9es sur la structure du syst\u00e8me nerveux : Chez l\u2019homme et chez les vert\u00e9br\u00e9s","author":"Ram\u00f3n y Cajal S.","year":"1894","unstructured":"S. Ram\u00f3n y Cajal, S. Ram\u00f3n y Cajal, L. Azoulay, Les nouvelles id\u00e9es sur la structure du syst\u00e8me nerveux : Chez l\u2019homme et chez les vert\u00e9br\u00e9s, Edition Fran\u00e7aise revue et augment\u00e9e par l\u2019auteur (C. Reinwald & Cie, 1894)."},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jphysparis.2016.11.007"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0590-4"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1093\/database\/baw001"},{"key":"e_1_3_4_57_2","unstructured":"X. Chen N. H. Guo A transcription regulator atlas identifies TOX3 as an Atoh1 co-activator in cerebellar development and tumorigenesis. GEO. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE312658. Deposited 5 December 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2527163123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T17:41:09Z","timestamp":1773855669000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2527163123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,18]]},"references-count":57,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2026,3,24]]}},"alternative-id":["10.1073\/pnas.2527163123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2527163123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,18]]},"assertion":[{"value":"2025-09-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2527163123"}}