Cross-talk between enhancers, structural elements and activating transcription factors maintains the 3D architecture and expression of the CFTR gene

Yin, Shiyi; NandyMazumdar, Monali; Paranjapye, Alekh; Harris, Ann

doi:10.1016/j.ygeno.2022.110350

Cited by 7 publications

(27 citation statements)

References 43 publications

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“…In WT 16HBE14o − cells the 5′ and 3′ TAD (+48.9 kb) boundaries interact, in addition to the −80.1 kb boundary interacting with the airway enhancers at −44 kb and −35 kb, the −20.9 kb insulator, the CFTR promoter and an element in intron 4 that we reported previously 30,32 (Figure 2A interactions between the −44 kb enhancer and the −20.9 kb viewpoint (Figure 3B, teal line). In general, and irrespective of changes to CFTR transcript levels, interaction profiles with the −20.9 kb viewpoint show a loss of interactions throughout the locus in the small deletion clones, reflecting a relaxation of the higher order structure of the CFTR locus, which is highly dependent on the −20.9 kb insulator element.…”

Section: Deletions Upstream Of the Cftr Promoter Variably Alter Cftr ...mentioning

confidence: 55%

“…The dominant enhancers include a relatively weak one in intron 1 (185 + 10 kb), 19,20,41 which works together with a much stronger one in intron 11 (1811 + 0.8 kb, RefSeq intron 12). 27,28,32 To investigate the effect of spacing on the intron 1 enhancer:promoter interactions, we next generated clones of Caco2 cells carrying one of two deletions between the CFTR promoter and this enhancer (Figure 5A).…”

Section: Intronic Deletions Have a Size-dependent Impact On Cftr Expr...mentioning

confidence: 99%

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The impact of genomic distance on enhancer‐promoter interactions at the CFTR locus

Kerschner,

Meckler,

Coatti

et al. 2024

J Cellular Molecular Medi

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We identified and characterized multiple cell‐type selective enhancers of the CFTR gene promoter in previous work and demonstrated active looping of these elements to the promoter. Here we address the impact of genomic spacing on these enhancer:promoter interactions and on CFTR gene expression. Using CRISPR/Cas9, we generated clonal cell lines with deletions between the −35 kb airway enhancer and the CFTR promoter in the 16HBE14o− airway cell line, or between the intron 1 (185 + 10 kb) intestinal enhancer and the promoter in the Caco2 intestinal cell line. The effect of these deletions on CFTR transcript abundance, as well as the 3D looping structure of the locus was investigated in triplicate clones of each modification. Our results indicate that both small and larger deletions upstream of the promoter can perturb CFTR expression and −35 kb enhancer:promoter interactions in the airway cells, though the larger deletions are more impactful. In contrast, the small intronic deletions have no effect on CFTR expression and intron 1 enhancer:promoter interactions in the intestinal cells, whereas larger deletions do. Clonal variation following a specific CFTR modification is a confounding factor particularly in 16HBE14o− cells.

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Section: Deletions Upstream Of the Cftr Promoter Variably Alter Cftr ...mentioning

confidence: 55%

Section: Intronic Deletions Have a Size-dependent Impact On Cftr Expr...mentioning

confidence: 99%

The impact of genomic distance on enhancer‐promoter interactions at the CFTR locus

Kerschner,

Meckler,

Coatti

et al. 2024

J Cellular Molecular Medi

Self Cite

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Section: Discussionmentioning

confidence: 99%

“…Transcription is the process by which RNA is synthesized according to the genomic sequence of DNA. The transcription process requires two key elements, the promoter and transcription factor binding to the promoter ( 18 , 36 , 37 ). Revealing the mechanisms by which an oncogene is regulated will help to further understand the process of tumorigenesis and progression, as well as to determine novel therapeutic targets ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

PLAU is associated with cell migration and invasion and is regulated by transcription factor YY1 in cervical cancer

Gao

Lu²,

et al. 2022

Oncol Rep

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“…Subsequent assays for monitoring gene expression and an analysis of higher order chromatin structure (4C-seq) highlighted the interaction between two cell type specific intronic enhancers, with loss of these enhancers resulting in an ablation of CFTR expression. Moreover, this mechanism, which is activated when the CREs are lost, involves the loss of CFTR activating transcription factors, including FOXA2 [ 54 ], and the loss of higher order chromatin structure. Furthermore, studies by the group of Stephanie Moisin identified four intestinal-specific CREs that are critical for regulation of CFTR expression in intestinal cells [ 55 ].…”

Section: Potential Molecular Mechanisms Involved In the Regulation Of...mentioning

confidence: 99%

CFTR and Gastrointestinal Cancers: An Update

Bhattacharya

Blankenheim

Scott

et al. 2022

JPM

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Cystic Fibrosis (CF) is a disease caused by mutations in the CFTR gene that severely affects the lungs as well as extra-pulmonary tissues, including the gastrointestinal (GI) tract. CFTR dysfunction resulting from either mutations or the downregulation of its expression has been shown to promote carcinogenesis. An example is the enhanced risk for several types of cancer in patients with CF, especially cancers of the GI tract. CFTR also acts as a tumor suppressor in diverse sporadic epithelial cancers in many tissues, primarily due to the silencing of CFTR expression via multiple mechanisms, but especially due to epigenetic regulation. This review provides an update on the latest research linking CFTR-deficiency to GI cancers, in both CF patients and in sporadic GI cancers, with a particular focus on cancer of the intestinal tract. It will discuss changes in the tissue landscape linked to CFTR-deficiency that may promote cancer development such as breakdowns in physical barriers, microbial dysbiosis and inflammation. It will also discuss molecular pathways and mechanisms that act upstream to modulate CFTR expression, such as by epigenetic silencing, as well as molecular pathways that act downstream of CFTR-deficiency, such as the dysregulation of the Wnt/β-catenin and NF-κB signaling pathways. Finally, it will discuss the emerging CFTR modulator drugs that have shown promising results in improving CFTR function in CF patients. The potential impact of these modulator drugs on the treatment and prevention of GI cancers can provide a new example of personalized cancer medicine.

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Cross-talk between enhancers, structural elements and activating transcription factors maintains the 3D architecture and expression of the CFTR gene

Cited by 7 publications

References 43 publications

The impact of genomic distance on enhancer‐promoter interactions at the CFTR locus

The impact of genomic distance on enhancer‐promoter interactions at the CFTR locus

PLAU is associated with cell migration and invasion and is regulated by transcription factor YY1 in cervical cancer

CFTR and Gastrointestinal Cancers: An Update

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