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For the cystic fibrosis transmembrane conductance regulator (CFTR) gene, tissue-specific expression, especially in the pancreas, remains poorly understood. Unraveling its regulation could clarify the clinical heterogeneity observed in cystic fibrosis and CFTR-related disorders. To understand the role of 3D chromatin architecture in establishing tissue-specific expression of the CFTR gene, we mapped chromatin interactions and epigenomic regulation in Capan-1 pancreatic cells. Candidate CREs are validated by luciferase reporter assay and CRISPR knock-out. We identified active CREs not only around the CFTR gene but also outside the topologically associating domain (TAD). We demonstrate the involvement of multiple CREs upstream and downstream of the CFTR gene and reveal a cooperative effect of the \u221244 kb, \u221235 kb, +15.6 kb, and +37.7 kb regions, which share common predicted transcription factor (TF) motifs. We also extend our analysis to compare 3D chromatin conformation in intestinal and pancreatic cells, providing valuable insights into the tissue specificity of CREs in regulating CFTR gene expression.<\/jats:p>","DOI":"10.3390\/ijms26083788","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T04:16:21Z","timestamp":1744863381000},"page":"3788","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cis-Regulation of the CFTR Gene in Pancreatic Cells"],"prefix":"10.3390","volume":"26","author":[{"given":"Clara","family":"Blotas","sequence":"first","affiliation":[{"name":"Univ Brest, Inserm, EFS, UMR 1078, GGB, F 29200 Brest, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana\u00efs","family":"Le Nabec","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne, 1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5396-8723","authenticated-orcid":false,"given":"M\u00e9gane","family":"Collobert","sequence":"additional","affiliation":[{"name":"Univ Brest, Inserm, EFS, UMR 1078, GGB, F 29200 Brest, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8829-3180","authenticated-orcid":false,"given":"Mattijs","family":"Bulcaen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium"},{"name":"Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8263-0350","authenticated-orcid":false,"given":"Marianne S.","family":"Carlon","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium"},{"name":"Leuven Viral Vector Core, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2325-0710","authenticated-orcid":false,"given":"Claude","family":"F\u00e9rec","sequence":"additional","affiliation":[{"name":"Univ Brest, Inserm, EFS, UMR 1078, GGB, F 29200 Brest, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Moisan","sequence":"additional","affiliation":[{"name":"Univ Brest, Inserm, EFS, UMR 1078, GGB, F 29200 Brest, France"},{"name":"Centre Hospitalier Universitaire Brest, F 29200 Brest, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"The ENCODE Project Consortium, Abascal, F., Acosta, R., Addleman, N.J., Adrian, J., Afzal, V., Aken, B., Ai, R., Akiyama, J.A., and Jammal, O.A. 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