CFTR gene regulation in pancreatic duct, bile duct and sweat gland
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ABSTRACT:
PROVIDER: PRJNA1196500 | ENA |
REPOSITORIES: ENA
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Project description:We examine cis-regulatory elements controlling expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in ductal eptihelial cells from pancreas, bile duct and sweat gland. Mutations in CFTR are associated with the inherited disorder cystic fibrosis. We identify several novel sites in addition to multiple elements seen in in other epithelial cell types.
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Project description:Millions of sweat glands required to maintain body temperature develop from embryonic ectoderm by a poorly defined mechanism. We present evidence for temporal cascade regulation of sweat gland development by Wnt, Eda and Shh pathways. The first stage, sweat gland induction, failed completely when Wnt/β-catenin signaling was blocked in skin epithelium, accompanied by sharp downregulation of Wnt, Eda and Shh pathway genes. In a meta-layer of regulation, Wnt antagonist Dkk4 appeared to operate on sweat gland induction in a negative feedback loop: Dkk4 was itself sharply downregulated in β-catenin-ablated mice, whereas its over-expression repressed Wnt target genes and significantly reduced gland numbers. Eda signaling succeeded Wnt, and activated downstream Shh pathway. Thus, in absence of Eda, Wnt pathway was still active and initial sweat gland pre-germs were seen but failed to develop germs, and dwonstream Shh pathway was repressed. When both Wnt and Eda were intact but Shh was ablated, early stage induction and subsequent duct formation occurred normally, but the final stage formation of secretory coil failed. Thus, sweat gland development shows a relay of regulatory steps, initiated by Wnt/β-catenin -- itself modulated by Dkk4 -- with subsequent tandem action of Eda and Shh pathways.
2014-08-20 | GSE50862 | GEO
Project description:Millions of sweat glands required to maintain body temperature develop from embryonic ectoderm by a poorly defined mechanism. We present evidence for temporal cascade regulation of sweat gland development by Wnt, Eda and Shh pathways. The first stage, sweat gland induction, failed completely when Wnt/?-catenin signaling was blocked in skin epithelium, accompanied by sharp downregulation of Wnt, Eda and Shh pathway genes. In a meta-layer of regulation, Wnt antagonist Dkk4 appeared to operate on sweat gland induction in a negative feedback loop: Dkk4 was itself sharply downregulated in ?-catenin-ablated mice, whereas its over-expression repressed Wnt target genes and significantly reduced gland numbers. Eda signaling succeeded Wnt, and activated downstream Shh pathway. Thus, in absence of Eda, Wnt pathway was still active and initial sweat gland pre-germs were seen but failed to develop germs, and dwonstream Shh pathway was repressed. When both Wnt and Eda were intact but Shh was ablated, early stage induction and subsequent duct formation occurred normally, but the final stage formation of secretory coil failed. Thus, sweat gland development shows a relay of regulatory steps, initiated by Wnt/?-catenin -- itself modulated by Dkk4 -- with subsequent tandem action of Eda and Shh pathways. Compared expression changes between WT and skin specific Dkk4 transgenic footpads at 2 developmental time points, E15.5 and E16.5. Data were duplicated with 2 sets of samples.
2014-08-20 | E-GEOD-50862 | biostudies-arrayexpress
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2020-11-19 | GSE156519 | GEO
Project description:Millions of sweat glands required to maintain body temperature develop from embryonic ectoderm by a poorly defined mechanism. We present evidence for temporal cascade regulation of sweat gland development by Wnt, Eda and Shh pathways. The first stage, sweat gland induction, failed completely when Wnt/β-catenin signaling was blocked in skin epithelium, accompanied by sharp downregulation of Wnt, Eda and Shh pathway genes. In a meta-layer of regulation, Wnt antagonist Dkk4 appeared to operate on sweat gland induction in a negative feedback loop: Dkk4 was itself sharply downregulated in β-catenin-ablated mice, whereas its over-expression repressed Wnt target genes and significantly reduced gland numbers. Eda signaling succeeded Wnt, and activated downstream Shh pathway. Thus, in absence of Eda, Wnt pathway was still active and initial sweat gland pre-germs were seen but failed to develop germs, and dwonstream Shh pathway was repressed. When both Wnt and Eda were intact but Shh was ablated, early stage induction and subsequent duct formation occurred normally, but the final stage formation of secretory coil failed. Thus, sweat gland development shows a relay of regulatory steps, initiated by Wnt/β-catenin -- itself modulated by Dkk4 -- with subsequent tandem action of Eda and Shh pathways.
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Project description:Assays in bile duct cancer patients showed 984 CNVs in 306 CNV regions (CNVR) distributed throughout all 22 chromosomes. Bile duct cancer patients had a mean of 21.8 gains and 19.2 losses of genes, with an average of 35.9 CNVRs per patient. Frequent sites of gains were at chromosomes 22q11.22, 2p11.2-p.11.1, 14q32.33 and 17q12, whereas frequent sites of losses were at 19q12-q13.43. Investigation of CNV in 24 bile duct cancer tissue samples
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Project description:Millions of sweat glands required to maintain body temperature develop from embryonic ectoderm by a poorly defined mechanism. We present evidence for temporal cascade regulation of sweat gland development by Wnt, Eda and Shh pathways. The first stage, sweat gland induction, failed completely when Wnt/β-catenin signaling was blocked in skin epithelium, accompanied by sharp downregulation of Wnt, Eda and Shh pathway genes. In a meta-layer of regulation, Wnt antagonist Dkk4 appeared to operate on sweat gland induction in a negative feedback loop: Dkk4 was itself sharply downregulated in β-catenin-ablated mice, whereas its over-expression repressed Wnt target genes and significantly reduced gland numbers. Eda signaling succeeded Wnt, and activated downstream Shh pathway. Thus, in absence of Eda, Wnt pathway was still active and initial sweat gland pre-germs were seen but failed to develop germs, and dwonstream Shh pathway was repressed. When both Wnt and Eda were intact but Shh was ablated, early stage induction and subsequent duct formation occurred normally, but the final stage formation of secretory coil failed. Thus, sweat gland development shows a relay of regulatory steps, initiated by Wnt/β-catenin -- itself modulated by Dkk4 -- with subsequent tandem action of Eda and Shh pathways. Compared expression changes between wild type and skin specific beta-catenin knockout footpads at 3 developmental time points, E15.5, E16.5 and E17.5. Data were duplicated with 2 sets of samples.
2014-08-20 | E-GEOD-50859 | biostudies-arrayexpress
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
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
Project description:Genome wide DNA methylation profiling of normal and tumor bile duct samples. The Illumina HumanMethylation450 BeadChip was used to obtain DNA methylation profiles across approximately 450,000 CpGs in 138 tumor bile duct samples and 4 normal bile duct samples.
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