Cis-Regulation of the CFTR Gene in Pancreatic Cells

Genome organization is essential for precise spatial and temporal gene expression and relies on interactions between promoters and distal cis-regulatory elements (CREs), which constitute ~8% of the human genome. 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 −44 kb, −35 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.

• Publication year

  2025

• Venue

  International Journal of Molecular Sciences

• Publication date

  2025-04-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.3390/ijms26083788PMID 40332394PMCID 12027686
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2014influential reference
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  1999influential reference
• A Regulatory Element in Intron 1 of the Cystic Fibrosis Transmembrane Conductance Regulator Gene (*)

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