Gene expression in early phases of Autosomal Dominant Polycystic Kidney Disease
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE13452 | GEO | 2008/12/28
SECONDARY ACCESSION(S): PRJNA110053
REPOSITORIES: GEO
Similar Datasets
Project description:Little is known about the genes involved in the initial cyst formation and disease progression in autosomal dominant polycystic kidney disease (ADPKD). To uncover the genetic determinants and molecular mechanisms of ADPKD, we analyzed 4-point time-series DNA microarrays from Pkd1L3/L3 mice to generate high-resolution gene expression profiles at different stages of disease progression. We found different characteristic gene expression signatures in the kidneys of Pkd1L3/L3 mice compared to age-matched controls during the initial phase of the disease. By postnatal week 1, the Pkd1L3/L3 kidney already had a distinctive gene expression pattern considerably different from the corresponding normal controls. The genes differentially expressed, either induced or repressed, in ADPKD are important in immune defense, cell structure and motility, cellular proliferation, apoptosis and metabolic processes, and include members of three pathways (Wnt, Notch, and BMP) involved in morphogenetic signaling. Further analysis of the gene expression profiles from the early stage of cystogenesis to end stage disease identified a possible gene network involved in the pathogenesis of ADPKD. A total of 13 microarray data sets were generated with RNA samples from age-matched control and disease littermates at the four time points, with at least three biological replicates for each time point (PNW1, n = 3; PNW2, n = 4; PNW3, n = 3; PNW3.5, n = 3). 13 2-color experiments including: 3 replicates of: Wt mice vs. Pkd1L3/L3 mice at PNW 1 4 replicates of: Wt mice vs. Pkd1L3/L3 mice at PNW 2 3 replicates of: Wt mice vs. Pkd1L3/L3 mice at PNW 3 3 replicates of: Wt mice vs. Pkd1L3/L3 mice at PNW 3.5
2008-12-28 | E-GEOD-13452 | biostudies-arrayexpress
Project description:Based on the dosage effect hypothesis, renal cysts could arise in transgenic murine models overexpressing either PKD1 or PKD2, which are causal genes responsible for autosomal dominant polycystic kidney disease (ADPKD). To prove whether PKD genes overexpression is a universal mechanism driving cystogenesis or is merely restricted to rodents, other animal models are required. Previously, we failed to observe any renal cysts in a PKD2 overexpression transgenic pig model partially due to epigenetic silencing of transgene. Thus, to explore the feasibility of pig models and identification potential affected genes/pathways related to ADPKD, LLC-PK1 cells with high PKD2 expression were generated. RNA-seq was performed and MYC, IER3, ADM were found to be commonly upregulated genes in different PKD2 overexpression cell models. MYC is a well-characterized factor contributing to cystogenesis, and ADM is a biomarker for chronic kidney disease. Thus, theses genes might be indicators of disease progression. Additionally, some ADPKD associated pathways, e.g., MAPK, were also enriched in the cells. Besides, GO analysis demonstrated proliferation, apoptosis, cell cycle regulation, which are hall marks of ADPKD were disturbed. Therefore, our experiment not only identified some biomarkers or indictors regarding ADPKD, but also demonstrated high PKD2 expression would like to drive cystogenesis in future porcine models.
2019-12-04 | GSE141355 | GEO
Project description:Autosomal Dominant Polycystic Kidney Disease (ADPKD; MIM ID’s 173900, 601313, 613095) leads to end stage kidney disease, caused by mutations in PKD1 or PKD2. Inactivation of Pkd1 before or after P13 in mice results in distinct early- or late-onset disease. Using a mouse model of ADPKD carrying floxed Pkd1 alleles disrupted using a tamoxifen-inducible Cre recombinase, transcriptomics and metabolomics were applied to follow disease progression in animals induced before P10. Network analysis suggests that Pkd1-cystogenesis does not cause developmental arrest and occurs in the context of gene networks similar to those that regulate/maintain normal kidney morphology/function. These analyses also predict metabolic pathways, notably those controlled by HNF4α, are key elements in postnatal kidney maturation and early steps of cyst formation. To test this hypothesis, metabolic networks were altered by inactivating Hnf4a and Pkd1. The Pkd1/Hnf4a double knock-out have significantly more cystic kidneys thus indicating that modulating metabolic pathways might be an effective therapeutic approach.
2012-11-29 | GSE32586 | GEO
Project description:Metabolic reprogramming is emerging as a key pathological contributor to the progression of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying dysregulated cellular metabolism in cystic cells remain elusive. Super-enhancers (SEs) are large clusters of transcriptional enhancers that drive robust expression of cell identity and disease genes. Here, we establish a prominent role for SEs in regulating metabolic gene expression and ADPKD progression. Characterization of cis-acting SE landscapes in cystic renal epithelial cells reveals extensive remodeling of SEs during cystogenesis. Gene ontology analysis indicates that SE-associated transcripts in the metabolic pathway category are most significantly enriched in cystic cells. Cystic cells are highly sensitive to the inhibition of cyclin-dependent kinase 7 (CDK7), a critical component of the trans-acting SE complex. THZ1, a specific CDK7 inhibitor, exerts a potent anti-cystogenesis effect in ADPKD cells and mouse models. Integrative analyses of transcriptomics and SE profiling identify AMP deaminase 3 (AMPD3) as a SE-driven metabolic gene. Up-regulation of AMPD3 in cystic cells results in reduced AMP level and decreased AMPK activity, while inhibition of AMPD3 suppresses cyst development in a zebrafish ADPKD model. In a cohort of ADPKD patients, CDK7 expression is frequently elevated, and its expression is significantly correlated with AMPD3 expression and disease severity. Taken together, our findings elucidate a mechanism by which SE controls metabolic gene transcription during cystogenesis, and identifies SE-driven metabolic reprogramming as a promising therapeutic target for ADPKD treatment.
2020-05-16 | GSE141279 | GEO
Project description:Metabolic reprogramming is emerging as a key pathological contributor to the progression of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying dysregulated cellular metabolism in cystic cells remain elusive. Super-enhancers (SEs) are large clusters of transcriptional enhancers that drive robust expression of cell identity and disease genes. Here, we establish a prominent role for SEs in regulating metabolic gene expression and ADPKD progression. Characterization of cis-acting SE landscapes in cystic renal epithelial cells reveals extensive remodeling of SEs during cystogenesis. Gene ontology analysis indicates that SE-associated transcripts in the metabolic pathway category are most significantly enriched in cystic cells. Cystic cells are highly sensitive to the inhibition of cyclin-dependent kinase 7 (CDK7), a critical component of the trans-acting SE complex. THZ1, a specific CDK7 inhibitor, exerts a potent anti-cystogenesis effect in ADPKD cells and mouse models. Integrative analyses of transcriptomics and SE profiling identify AMP deaminase 3 (AMPD3) as a SE-driven metabolic gene. Up-regulation of AMPD3 in cystic cells results in reduced AMP level and decreased AMPK activity, while inhibition of AMPD3 suppresses cyst development in a zebrafish ADPKD model. In a cohort of ADPKD patients, CDK7 expression is frequently elevated, and its expression is significantly correlated with AMPD3 expression and disease severity. Taken together, our findings elucidate a mechanism by which SE controls metabolic gene transcription during cystogenesis, and identifies SE-driven metabolic reprogramming as a promising therapeutic target for ADPKD treatment.
2020-05-16 | GSE141280 | GEO
Project description:Metabolic reprogramming is emerging as a key pathological contributor to the progression of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying dysregulated cellular metabolism in cystic cells remain elusive. Super-enhancers (SEs) are large clusters of transcriptional enhancers that drive robust expression of cell identity and disease genes. Here, we establish a prominent role for SEs in regulating metabolic gene expression and ADPKD progression. Characterization of cis-acting SE landscapes in cystic renal epithelial cells reveals extensive remodeling of SEs during cystogenesis. Gene ontology analysis indicates that SE-associated transcripts in the metabolic pathway category are most significantly enriched in cystic cells. Cystic cells are highly sensitive to the inhibition of cyclin-dependent kinase 7 (CDK7), a critical component of the trans-acting SE complex. THZ1, a specific CDK7 inhibitor, exerts a potent anti-cystogenesis effect in ADPKD cells and mouse models. Integrative analyses of transcriptomics and SE profiling identify AMP deaminase 3 (AMPD3) as a SE-driven metabolic gene. Up-regulation of AMPD3 in cystic cells results in reduced AMP level and decreased AMPK activity, while inhibition of AMPD3 suppresses cyst development in a zebrafish ADPKD model. In a cohort of ADPKD patients, CDK7 expression is frequently elevated, and its expression is significantly correlated with AMPD3 expression and disease severity. Taken together, our findings elucidate a mechanism by which SE controls metabolic gene transcription during cystogenesis, and identifies SE-driven metabolic reprogramming as a promising therapeutic target for ADPKD treatment.
2020-05-16 | GSE146714 | GEO
Project description:Autosomal Dominant Polycystic Kidney Disease (ADPKD; MIM ID’s 173900, 601313, 613095) leads to end stage kidney disease, caused by mutations in PKD1 or PKD2. Inactivation of Pkd1 before or after P13 in mice results in distinct early- or late-onset disease. Using a mouse model of ADPKD carrying floxed Pkd1 alleles disrupted using a tamoxifen-inducible Cre recombinase, transcriptomics and metabolomics were applied to follow disease progression in animals induced before P10. Network analysis suggests that Pkd1-cystogenesis does not cause developmental arrest and occurs in the context of gene networks similar to those that regulate/maintain normal kidney morphology/function. These analyses also predict metabolic pathways, notably those controlled by HNF4α, are key elements in postnatal kidney maturation and early steps of cyst formation. To test this hypothesis, metabolic networks were altered by inactivating Hnf4a and Pkd1. The Pkd1/Hnf4a double knock-out have significantly more cystic kidneys thus indicating that modulating metabolic pathways might be an effective therapeutic approach. We crossed fifth-generation C57/BL6 Pkd1cond mice to fifth-generation C57/BL6 tamoxifen-Cre (B6.Cg-Tg(Cre/Esr1)5Amc/J mice (stock 004682), Jackson Laboratories) and C57/BL6 congenic B6.129S4-Gt(ROSA)26Sortm1Sor/J (stock 003474, Jackson Laboratories) to produce Pkd1 conditional mice with TamCre (mutant) or without TamCre (control). We induced Cre recombinase activity in mice < 10 days of age by intraperitoneally injecting nursing mothers with tamoxifen (10 mg/40 g) , and harvested kidney samples of control and mutant (34 and 36 animals, respectively) between the ages of 11 and 24 days. Postprocessed files (expression p value<0.05; quantile normalized; merged and corrected for batch-effect using COMBAT) linked below as supplementary files.
2012-11-29 | E-GEOD-32586 | biostudies-arrayexpress
Project description:Formation of biomolecular condensates by phase separation has recently emerged as a new principle for regulating gene expression in response to extracellular signaling. However, the molecular mechanisms underlying the coupling of signal transduction and gene activation through condensate formation, and how dysregulation of these mechanisms contributes to disease progression, remain elusive. Here we report that CREB-regulated transcription coactivator 2 (CRTC2) translocates to the nucleus and forms phase-separated condensates upon activation of cAMP signaling. We show that intranuclear CRTC2 interacts with positive transcription elongation factor b (P-TEFb) and activates P-TEFb by disrupting the inhibitory 7SK snRNP complex. Aberrantly elevated cAMP signaling plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD). We find that CRTC2 localizes to the nucleus and forms condensates in cystic epithelial cells of both mouse and human ADPKD kidneys. Genetic depletion of CRTC2 suppresses cyst growth in an orthologous ADPKD mouse model. Using integrative transcriptomic and cistromic analyses, we identify CRTC2-regulated cystogenesis-associated genes, whose activation depends on CRTC2 condensate-facilitated P-TEFb recruitment and the release of paused RNA polymerase II. Together, our findings elucidate a mechanism by which CRTC2 nuclear condensation conveys cAMP signaling to transcription elongation activation and thereby promotes cystogenesis in ADPKD.
2021-12-28 | GSE173695 | GEO
Project description:We showed that pharmacological inhibition of P-TEFb attenuated cyst development in ADPKD mouse models. Genome-wide analyses demonstrated that P-TEFb inhibition abrogated transcriptional pause release and suppressed a pathologic gene expression program during cystogenesis. This work revealed a mechanism by which aberrant activation of P-TEFb-mediated transcription elongation promotes cystogenesis in ADPKD.
2019-06-20 | GSE128522 | GEO
Project description:We showed that pharmacological inhibition of P-TEFb attenuated cyst development in ADPKD mouse models. Genome-wide analyses demonstrated that P-TEFb inhibition abrogated transcriptional pause release and suppressed a pathologic gene expression program during cystogenesis. This work revealed a mechanism by which aberrant activation of P-TEFb-mediated transcription elongation promotes cystogenesis in ADPKD.
2019-06-20 | GSE128521 | GEO