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In the gut tube, the small intestine absorbs nutrients, whereas the colon absorbs electrolytes. In a striking display of inherent plasticity, adult colonic mucosa lacking the chromatin factor SATB2 is converted to small intestine. Using proteomics and CRISPR-Cas9 screening, we identify MTA2 as a crucial component of the molecular machinery that, together with SATB2, restrains colonic plasticity. MTA2 loss in the adult mouse colon activated lipid absorptive genes and functional lipid uptake. Mechanistically, MTA2 co-occupies DNA with HNF4A, an activating pan-intestinal transcription factor (TF), on colonic chromatin. MTA2 loss leads to HNF4A release from colonic chromatin, and accumulation on small intestinal chromatin. SATB2 similarly restrains colonic plasticity through an HNF4A-dependent mechanism. Our study provides a generalizable model of lineage plasticity in which broadly-expressed TFs are retained on tissue-specific enhancers to maintain cell identity and prevent activation of alternative lineages, and their release unleashes plasticity.<\/jats:p>","DOI":"10.1038\/s41467-024-47738-y","type":"journal-article","created":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T14:02:04Z","timestamp":1714226524000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A MTA2-SATB2 chromatin complex restrains colonic plasticity toward small intestine by retaining HNF4A at colonic chromatin"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5958-2653","authenticated-orcid":false,"given":"Wei","family":"Gu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8571-4667","authenticated-orcid":false,"given":"Xiaofeng","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratik N. 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OMICS 16, 284\u2013287 (2012).","journal-title":"OMICS"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-47738-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-47738-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-47738-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T15:02:12Z","timestamp":1714230132000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-47738-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,27]]},"references-count":56,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["47738"],"URL":"https:\/\/doi.org\/10.1038\/s41467-024-47738-y","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.12.15.520587","asserted-by":"object"}]},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,27]]},"assertion":[{"value":"5 December 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 April 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 April 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Human organoids were obtained from the In Vivo Animal and Human Studies Core at the University of Michigan Center for Gastrointestinal Research. All studies involving human samples were approved by the ethics committee at the University of Michigan. Informed consent was obtained from the participants and or parents\/guardians for these studies. The research work complied with all relevant ethical regulations. All procedures involving mice were conducted under the IACUC protocol 2018-0050 approved by Weill Cornell Medical College.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"3595"}}