Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CFTR Represses a PDX1 Axis to Govern Pancreatic Ductal Cell Fate [Bulk ATAC-seq]

ABSTRACT: 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.

ORGANISM(S): Mustela putorius furo

PROVIDER: GSE264021 | GEO | 2024/09/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

CFTR Represses a PDX1 Axis to Govern Pancreatic Ductal Cell Fate [scRNA-seq]

Project description: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.

2024-09-18 | GSE264022 | GEO

CFTR Represses a PDX1 Axis to Govern Pancreatic Ductal Cell Fate [Bulk RNA-seq]

2024-09-18 | GSE264019 | GEO

Secretome and Proteome of WT and CFTR-KO pancreatic duct epithelial cells

Project description:Loss of CFTR function in the pancreatic duct leads to dysregulated luminal pH causing premature activation of digestive enzymes and tissue necrosis. Drastic alterations in pancreatic tissue architecture and cellular composition changes the microenvironment of the islets. Given that CFTR is expressed in the pancreatic ducts, we hypothesized that loss of functional CFTR impacts islet function by modifying the ductal secretome. To this end, we developed a long-term in vitro pancreatic duct epithelial cell culture system and polarized both WT and CFTR-KO (CF) ferret duct epithelial cells. We profiled the apical and basolateral secretome, and the cellular proteome of both WT and CF duct epithelium using quantitative mass spectrometry. Bioinformatic analysis of differentially secreted proteins mapped to their cognate receptors provided a list of putative paracrine interactions that affect islet function. Signaling pathways and upstream regulators that alter the secretome and cellular proteome profile were computationally mined to characterize disease causing mechanisms. In this study, we provide a proteomic roadmap of perturbed autocrine and paracrine signals from the CF pancreatic duct.

2021-05-27 | PXD025126 | Pride

The role of CFTR in islet function

Project description:Cystic fibrosis (CF)-related diabetes (CFRD) is an increasingly common and devastating comorbidity of CF, affecting ~35% of adults with CF. However, the underlying causes of CFRD are unclear. Here, we examined cystic fibrosis transmembrane conductance regulator (CFTR) islet expression and whether the CFTR participates in islet endocrine cell function using murine models of b cell CFTR deletion, and normal and CF human pancreas and islets. Specific deletion of CFTR from murine b cells did not affect b cell function. In human islets, CFTR mRNA was minimally expressed, and CFTR protein/electrical activity was not detected. Isolated CF/CFRD islets demonstrated appropriate insulin and glucagon secretion with few changes in key islet-regulatory transcripts. Furthermore, ~65% of b cell area was lost in CF donors, compounded by pancreatic remodeling and immune infiltration of the islet. These results indicate that CFRD is not caused by intrinsic islet dysfunction from CFTR mutation, but rather, by b cell loss and intra-islet inflammation in the setting of a complex pleiotropic disease

2018-04-25 | GSE110935 | GEO

CFTR deficiency modulates the activity of endothelial mechanosensitive channels TRPV4 and PIEZO1; and drives endothelial barrier failure.

Project description:Cystic fibrosis (CF) is a life-shortening genetic disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite reports of CFTR expression on endothelial cells, pulmonary vascular perturbations, and perfusion deficit in CF patients, the mechanism of pulmonary vascular disease in CF remains unclear. Here, we describe loss of small pulmonary blood vessels in CF patients with severe lung disease. Using a vessel-on-a-chip model, we establish a shear stress-dependent mechanism of endothelial barrier failure in CF involving calcium-permeable mechanosensitive channel TRPV4. Furthermore, we demonstrate that CFTR deficiency downregulates the function of PIEZO1, another calcium-permeable mechanosensitive channel involved in angiogenesis and wound repair, and further exacerbates loss of small pulmonary blood vessels. We show that CFTR directly interacts with PIEZO1 and enhances its function, and that CFTR deficiency reduces PIEZO1 activity. Our study identifies key cellular targets to mitigate loss of small pulmonary blood vessels in CF.

2024-09-18 | GSE244214 | GEO

Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescue

Project description:Cystic fibrosis (CF), caused by mutations to CFTR, leads to severe and progressive lung disease. The most common mutant, ΔF508-CFTR, undergoes proteasomal degradation, depleting its anion channel function. “Proteostasis” pathways, i.e. those relevant to protein processing and trafficking, are altered in cells with ΔF508-CFTR and can be modulated to partially rescue protein function. However, many details regarding proteostasis modulation, and its relevance to CF and ΔF508-CFTR rescue, remain poorly understood. To shed light on this, we re-analyzed public datasets characterizing transcription in CF vs. non-CF epithelia from human and pig airways, and also profiled established temperature, genetic, and chemical interventions that rescue ΔF508-CFTR. Meta-analysis yielded a core disease signature and two core rescue signatures. To interpret these, we compiled proteostasis pathways and an original “CFTR Gene Set Library”. The disease signature revealed differential regulation of mTORC1 signaling, endocytosis, and proteasomal degradation. Overlaying functional genomics data identified candidate mediators of low-temperature rescue, while multiple rescue strategies converged on activation of unfolded protein response pathways. Remarkably, however, C18, an analog of the CFTR corrector compound Lumacaftor, induced minimal transcriptional perturbation despite its rescue activity. This work elucidates the involvement of proteostasis in both disease and rescue perturbations while highlighting that not all CFTR rescue interventions act on transcription.

2020-12-01 | GSE142610 | GEO

Eccrine sweat proteomics for the diagnosis of cystic fibrosis

Project description:In clinical routine, the diagnosis of cystic fibrosis (CF) is still a challenge due to the limitations of diagnosis guidelines and tests. A diagnosis test of choice, the sweat test measures eccrine sweat chloride concentration as a byproduct of the eccrine sweat gland CFTR function. Despite the combined use of CFTR genotyping and direct physiologic testing of CFTR function, reports of inconclusive diagnosis justified the need for alternative tests and new biomarkers. Meanwhile, eccrine sweat composition has already been linked to disease-specific profiles of non-electrolytes (i.e. proteins, peptides and metabolites). In this study, we analyzed sweat samples from 28 healthy volunteers and 14 CF patients by UHPLC-Q-Orbitrap-based Shotgun proteomics, to address CF-related changes in sweat protein composition and abundance. Over 1000 proteins were identified and quantified in a label-free manner. Beside similar protein composition, enrichment and functional classifications, HV and CF samples were grouped apart since protein abundance profiles were significantly correlated with CF status and degree of severity (ΔF508 homozygous and pancreatic insufficiency onset). Four-hundred and two proteins in CF-specific abundance, 68 proteins in genotype-specific abundance and 71 proteins in abundance related to pancreatic status, respectively, highlighted eccrine gland cell perturbations in protein biosynthesis & trafficking, CFTR proteostasis & membrane stability, cell-cell adherence, membrane integrity & cytoskeleton crosstalk. Cytoskeleton-related biomarkers were of utmost interest because of consistent abundances between CF sweat and other CF tissues. Nine clinical CF diagnosis biomarker (CUTA, ARG1, EZR, AGA, FLNA, MAN1A1, MIA3, LFNG, SIAE) and 5 CF severity biomarker (ARG1, GPT, MDH2, EML4 (ΔF508 homozygous), MGAT1 (pancreatic insufficiency)) candidates were deemed suitable for further verification.

2022-10-13 | PXD028518 | Pride

RPTOR, a novel target of miR-155, regulates the fibrotic phenotype of cystic fibrosis lung epithelium by upregulating CTGF

Project description:Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the most frequent of which is F508del-CFTR. CF is characterized by excessive secretion of pro-inflammatory chemokines into the airway lumen, inducing a highly inflammatory cellular phenotype. This process triggers fibrosis, causing airway destruction and leading to high morbidity and mortality. We previously reported that miR-155 is up-regulated in CF lung epithelial cells, but the molecular mechanisms by which miR-155 affects the disease phenotype is not understood. Here we report that the protein RPTOR (regulatory associated protein of mTOR, complex 1) is a novel target of miR-155 in CF lung epithelial cells. The suppression of RPTOR expression and subsequent activation of TGF-β signaling resulted in the induction of fibrosis by up-regulation of connective tissue growth factor (CTGF) in CF lung epithelial cells. Thus, we propose that miR-155 can regulate fibrosis of CF lungs through the RPTOR-TGF-β-CTGF axis, highlighting its potential value in CF therapy.

2024-07-16 | GSE80798 | GEO

Expression data from human bronchial epithelial cells

Project description:The F508del mutation, the most frequent in cystic fibrosis (CF), impairs the maturation of the CFTR chloride channel. The F508del defect can be partially overcome at low temperature (27 Â°C) or with pharmacological correctors. The rescue elicited by low temperature may involve a direct stabilization of mutant CFTR protein and/or a change in cell transcriptome that creates a more favorable proteostasis environment. To assess the effect of low temperature on gene expression we investigated the transcriptome of bronchial epithelial cells derived from CF with F508del mutation. Cells were kept under control conditions or incubated at 27 Â°C. Microarray data indicate that hypothermia induces a profound and global change in gene expression that may be in part responsible for rescue of F508del-CFTR. Bronchial epithelial cells from cystic fibrosis patients homozygotes for F508del mutation were isolated. Cells differentiated as epithelial monolayers on porous membranes (Snapwell inserts) were incubated for 24 hours at 27 Â°C or kept under control conditions. Rescue of mutant CFTR channel by low temperature was checked by measuring transepithelial chloride currents with the Ussing chamber technique. Total RNA was extracted from treated and control cells to assess changes in gene expression with microarrays.

2016-07-01 | E-GEOD-70442 | biostudies-arrayexpress

Expression data from human bronchial epithelial cells

2016-07-01 | GSE70442 | GEO