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| Status |
Public on Sep 18, 2024 |
| Title |
CFTR Represses a PDX1 Axis to Govern Pancreatic Ductal Cell Fate [Bulk ATAC-seq] |
| Organism |
Mustela putorius furo |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Inflammation, acinar cell destruction, and ductal cell hyperplasia drive pancreatic remodeling in newborns with cystic fibrosis (CF) lacking a functional CFTR channel. In neonatal CF ferrets, these changes are associated with a transient phase of glucose intolerance that involves islet destruction and subsequent regeneration near hyperplastic ducts. Little is known about the phenotypic changes in CF ductal epithelium and its potential impact on islet function. Using bulk RNA-seq, scRNA-seq, and ATAC-seq on CF ferret models, we demonstrate that ductal CFTR protein constrains PDX1 expression by maintaining PTEN and GSK3b activation. In the absence of CFTR protein, centroacinar cells (or terminal ductal cells) adopted a bi-potent progenitor-like state associated with enhanced WNT/b-Catenin, TGFb and AKT signaling. Notably, using in vitro and in vivo hypomorphic models of mutant CFTR expression, we show that the level of CFTR protein, not its channel function, regulates PDX1 expression. Thus, this study has discovered a cell-autonomous CFTR-dependent mechanism by which CFTR mutations that produced little to no protein could impact pancreatic exocrine/endocrine remodeling in people with CF.
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| Overall design |
Bulk ATAC-seq on differentiated WT and CF ferret PDE cultures grown at ALI
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| Contributor(s) |
Wells KL, Rotti PG, Englehardt JF |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Apr 15, 2024 |
| Last update date |
Sep 19, 2024 |
| Contact name |
Kristen Wells |
| E-mail(s) |
kristen.wells-wrasman@cuanschutz.edu
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| Organization name |
University of Colorado Anschutz
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| Department |
Barbara Davis Center
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| Lab |
Barbara Davis Center
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| Street address |
1775 Aurora Ct,
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| City |
Aurora |
| State/province |
CO |
| ZIP/Postal code |
80045 |
| Country |
USA |
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| Platforms (1) |
| GPL34388 |
Illumina HiSeq 4000 (Mustela putorius furo) |
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| Samples (7)
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| Relations |
| BioProject |
PRJNA1100558 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE264021_Diffbind_bindingmatrix.bed.gz |
3.2 Mb |
(ftp)(http) |
BED |
| GSE264021_RAW.tar |
13.4 Mb |
(http)(custom) |
TAR (of BED) |
SRA Run Selector |
| Raw data are available in SRA |
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