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Importantly, <jats:italic>THRA<\/jats:italic> is upregulated in colorectal cancers, particularly in the high\u2010Wnt molecular subtype. The basis of this specific and\/or altered expression pattern has remained unknown. To define the mechanisms controlling <jats:italic>THRA<\/jats:italic> transcription and TR\u03b11 expression, we used multiple <jats:italic>in\u2009vitro<\/jats:italic> and <jats:italic>ex\u2009vivo<\/jats:italic> approaches. Promoter analysis demonstrated that transcription factors important for crypt homeostasis and altered in colorectal cancers, such as transcription factor 7\u2010like 2 (TCF7L2; Wnt pathway), recombining binding protein suppressor of hairless (RBPJ; Notch pathway), and homeobox protein CDX2 (epithelial cell identity), modulate <jats:italic>THRA<\/jats:italic> activity. Specifically, although TCF7L2 and CDX2 stimulated <jats:italic>THRA<\/jats:italic>, RBPJ induced its repression. In\u2010depth analysis of the Wnt\u2010dependent increase showed direct regulation of the <jats:italic>THRA<\/jats:italic> promoter in cells and of TR\u03b11 expression in murine enteroids. Given our previous results on the control of the Wnt pathway by TR\u03b11, our new results unveil a complex regulatory loop and synergy between these endocrine and epithelial\u2010cell\u2010intrinsic signals. Our work describes, for the first time, the regulation of the <jats:italic>THRA<\/jats:italic> gene in specific cell and tumor contexts.<\/jats:p>","DOI":"10.1002\/1878-0261.13298","type":"journal-article","created":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T12:30:01Z","timestamp":1659270601000},"page":"3975-3993","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Regulation of the <i>THRA<\/i> gene, encoding the thyroid hormone nuclear receptor <scp>TR\u03b11<\/scp>, in intestinal lesions"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4888-7857","authenticated-orcid":false,"given":"Maria Virginia","family":"Giolito","sequence":"first","affiliation":[{"name":"Inserm, IRFAC\/UMR\u2010S1113, FMTS, Universit\u00e9 de Strasbourg  France"},{"name":"INSERM U1052, CNRS UMR5286, Centre de Recherche en Canc\u00e9rologie de Lyon  France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Th\u00e9o","family":"La Rosa","sequence":"additional","affiliation":[{"name":"INSERM U1052, CNRS UMR5286, Centre de Recherche en Canc\u00e9rologie de Lyon  France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2412-7618","authenticated-orcid":false,"given":"Diana","family":"Farhat","sequence":"additional","affiliation":[{"name":"Inserm, IRFAC\/UMR\u2010S1113, FMTS, Universit\u00e9 de Strasbourg  France"},{"name":"INSERM U1052, CNRS UMR5286, Centre de Recherche en Canc\u00e9rologie de Lyon  France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serguei","family":"Bodoirat","sequence":"additional","affiliation":[{"name":"Inserm, IRFAC\/UMR\u2010S1113, FMTS, Universit\u00e9 de Strasbourg  France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriela D. 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