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Here, we dissected the biology of entero-hepato mTECs, mimetic cells expressing gut- and liver-associated transcripts. Entero-hepato mTECs conserved their thymic identity yet accessed wide swaths of enterocyte chromatin and transcriptional programs via the transcription factors Hnf4\u03b1 and Hnf4\u03b3. Deletion of Hnf4\u03b1 and Hnf4\u03b3 in TECs ablated entero-hepato mTECs and downregulated numerous gut- and liver-associated transcripts, with a primary contribution from Hnf4\u03b3. Loss of Hnf4 impaired enhancer activation and CTCF redistribution in mTECs but did not impact Polycomb-mediated repression or promoter-proximal histone marks. By single-cell RNA sequencing, Hnf4 loss produced three distinct effects on mimetic cell state, fate, and accumulation. Serendipitously, a requirement for Hnf4 in microfold mTECs was discovered, which exposed a requirement for Hnf4\u03b3 in gut microfold cells and the IgA response. Study of Hnf4 in entero-hepato mTECs thus revealed mechanisms of gene control in the thymus and periphery alike.<\/jats:p>","DOI":"10.1084\/jem.20230461","type":"journal-article","created":{"date-parts":[[2023,6,17]],"date-time":"2023-06-17T02:20:47Z","timestamp":1686968447000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["Hnf4 activates mimetic-cell enhancers to recapitulate gut and liver development within the thymus"],"prefix":"10.1084","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9434-5207","authenticated-orcid":true,"given":"Daniel A.","family":"Michelson","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03wevmz92","id-type":"ROR","asserted-by":"publisher"}],"name":"Harvard Medical School 1 Department of Immunology, , Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6117-6438","authenticated-orcid":true,"given":"Chong","family":"Zuo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03wevmz92","id-type":"ROR","asserted-by":"publisher"}],"name":"Harvard Medical School 1 Department of Immunology, , Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4082-4330","authenticated-orcid":true,"given":"Michael","family":"Verzi","sequence":"additional","affiliation":[{"name":"Human Genetics Institute of New Jersey, Rutgers University 2 Department of Genetics, , Piscataway, NJ, USA"},{"name":"Rutgers Cancer Institute of New Jersey, Rutgers University 3 , New Brunswick, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1172-6555","authenticated-orcid":true,"given":"Christophe","family":"Benoist","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03wevmz92","id-type":"ROR","asserted-by":"publisher"}],"name":"Harvard Medical School 1 Department of Immunology, , Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6110-4626","authenticated-orcid":true,"given":"Diane","family":"Mathis","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03wevmz92","id-type":"ROR","asserted-by":"publisher"}],"name":"Harvard Medical School 1 Department of Immunology, , Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2023,7,3]]},"reference":[{"key":"2023070314283775100_bib1","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.cell.2009.12.030","article-title":"Aire\u2019s partners in the molecular control of immunological tolerance","volume":"140","author":"Abramson","year":"2010","journal-title":"Cell"},{"key":"2023070314283775100_bib2","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.1126\/science.1075958","article-title":"Projection of an immunological self shadow within the thymus by the aire protein","volume":"298","author":"Anderson","year":"2002","journal-title":"Science"},{"key":"2023070314283775100_bib3","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1038\/ni816","article-title":"Origin of regulatory T cells with known specificity for antigen","volume":"3","author":"Apostolou","year":"2002","journal-title":"Nat. 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