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Super-enhancers (SEs) are large clusters of regulatory elements densely bound by transcription factors (TFs) and cofactors that drive high-level expression of genes controlling cell identity and fate, yet their roles in intestinal epithelial identity and differentiation remain unclear. Here, we generate a spatiotemporal map of SEs in the small intestine, identifying compartment-specific SEs that define crypt and villus programs. Using mouse genetic models, we identify CDX2, HNF4, and SMAD4 as core TFs orchestrating SE-driven transcriptional networks essential for epithelial differentiation. CDX2 is required for SE integrity, and its loss causes widespread SE collapse and silencing of intestinal identity genes. We further demonstrate SE remodeling during colorectal cancer, in which HNF4 and SMAD4 function as SE-associated tumor suppressors that restrain oncogenic enhancer programs. Together, our findings establish SEs as central regulators of intestinal architecture, epithelial fidelity, and tumor progression.<\/jats:p>","DOI":"10.1093\/nar\/gkag634","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T12:31:38Z","timestamp":1781613098000},"source":"Crossref","is-referenced-by-count":0,"title":["Dynamics and master transcription factors dependence of intestinal super-enhancers during differentiation and oncogenesis"],"prefix":"10.1093","volume":"54","author":[{"given":"Wenxin","family":"Fang","sequence":"first","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University , Nanjing 210031 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuya","family":"Huang","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University , Nanjing 210031 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoxuan","family":"Xiao","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University , Nanjing 210031 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangling","family":"Wei","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University , Nanjing 210031 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University , Nanjing 210031 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Genetics, Rutgers University , Piscataway, NJ 08854 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zou","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University , Nanjing 210031 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P","family":"Verzi","sequence":"additional","affiliation":[{"name":"Department of Genetics, Rutgers University , Piscataway, NJ 08854 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0671-7312","authenticated-orcid":false,"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7812-508X","authenticated-orcid":false,"given":"Lei","family":"Chen","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University , Nanjing 210031 ,","place":["China"]},{"name":"Institute of Microphysiological Systems, Southeast University , Nanjing 211189 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"2026062504480296200_B1","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/nrm3951","article-title":"The Mediator complex: a central integrator of transcription","volume":"16","author":"Allen","year":"2015","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026062504480296200_B2","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1016\/j.tig.2012.02.008","article-title":"Enhancers as information integration hubs in development: lessons from genomics","volume":"28","author":"Buecker","year":"2012","journal-title":"Trends 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