Epigenetic silencing of PKD1 in autosomal dominant polycystic kidney disease
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE35831 | GEO | 2012/02/16
SECONDARY ACCESSION(S): PRJNA151897
REPOSITORIES: GEO
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Project description:ADPKD (Autosomal dominant polycystic kidney disease) is the most common inherited disorders and is characterized by growth of numerous cysts filled with fluid in the kidneys. Ultimately, it leads to kidney failure. The mutations of PKD1 and PKD2 account for approximately 85 and 15 percent of ADPKD, respectively. However, the mechanisms related to genetic mutation of PKD1 and PKD2 are still unclear. To investigate altered gene expression levels, Affymetrix microarray was performed using the kidney tissue from normal and ADPKD patients. Total RNAs were isolated from kidney of human normal (49 years old/ male) and ADPKD patients (62 years old/ male, 67 years old/ male) using NucleoSpin® RNA Kit (MACHEREY-NAGEL) according to the manufacturer’s instructions. We used tha Affymetrix GeneChip Human Gene 1.0 ST Array. Per RNA sample, 300 ng was used as the input into the Affymetrix procedure as recommended by the manufacturer's protocol.
2012-02-16 | E-GEOD-35831 | biostudies-arrayexpress
Project description:Polycystic Kidney Disease (PKD) is a genetic disease of the kidney characterized by the gradual replacement of normal kidney parenchyma by fluid-filled cysts and fibrotic tissue. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in the PKD1 or PKD2 gene. Here we present an RNASeq experiment designed to investigate the effect of a kidney specific and Tamoxifen inducible knockout of the Pkd1 gene in mice. The Pkd1cko mice were harvested at different time points 2-weeks, 3-weeks, 5-weeks, 10.5-weeks, 11-weeks and 15-weeks after gene inactivation.
2019-12-24 | E-MTAB-8086 | biostudies-arrayexpress
Project description:Polycystic Kidney Disease (PKD) is a genetic disease of the kidney characterized by the gradual replacement of normal kidney parenchyma by fluid-filled cysts and fibrotic tissue. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in the PKD1 or PKD2 gene. Here we present an RNASeq experiment designed to investigate the effect of a kidney specific and Tamoxifen inducible knockout of the Pkd1 gene in mice. 7 mice were grouped into two groups, 4 Tamoxifen treated mice which develop an adult onset Polycystic Kidney Disease phenotype and 3 untreated mice which have WT phenotype.
2016-06-01 | E-MTAB-4086 | biostudies-arrayexpress
Project description:Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating disease that is characterized by the accumulation of numerous fluid-filled cysts in the kidney. ADPKD is primarily caused by mutations in two genes, PKD1 and PKD2. Long noncoding RNAs (lncRNA) – defined by a length >200 nucleotides and absence of a long open reading frame – have recently emerged as epigenetic regulators of development and disease; however, their involvement in PKD has not been explored previously. Here, we performed deep RNA sequencing to identify lncRNAs that are dysregulated in two orthologous mouse models of ADPKD (kidney-specific Pkd1 and Pkd2 mutant mice). We identified a kidney- specific, evolutionarily-conserved lncRNA called Hoxb3os that was downregulated in cystic kidneys from Pkd1 and Pkd2 mutant mice. The human ortholog HOXB3-AS1 was downregulated in cystic kidneys from ADPKD patients. Hoxb3os was highly expressed in renal tubules in adult wild- type mice, whereas its expression was lost in the cyst epithelium of mutant mice. To investigate the function of Hoxb3os, we utilized CRISR/Cas9 to knockout its expression in mIMCD3 cells. Deletion of Hoxb3os resulted in increased phosphorylation of mTOR and its downstream targets, including p70 S6 kinase, ribosomal protein S6, and the translation repressor 4E-BP1. Consistent with activation of mTORC1 signaling, Hoxb3os mutant cells displayed increased mitochondrial respiration. The Hoxb3os mutant phenotype was partially rescued upon re- expression of Hoxb3os in knockout cells. These findings identify Hoxb3os as a novel lncRNA that is downregulated in ADPKD and regulates mTOR signaling and mitochondrial respiration.
2018-04-30 | GSE108864 | GEO
Project description:Background: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Methods: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Results: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Conclusions: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways.
2021-07-15 | GSE179947 | GEO
Project description:To elucidate the molecular pathways that modulate renal cyst growth in autosomal dominant polycystic kidney disease (ADPKD) Keywords: Disease state analysis We performed global gene profiling on renal cysts of different size (small cysts: less than 1 ml, n=5; medium cysts: between 10-25 ml, n=5; large cysts: greater than 50 ml, n=3) and minimally cystic tissue (MCT, n=5) from five PKD1 polycystic kidneys. Additionally, non-cancerous renal cortical tissue from three nephrectomized kidneys with isolated renal cell carcinoma was used as normal control tissue (n=3). This dataset is part of the TransQST collection.
2009-08-14 | E-GEOD-7869 | biostudies-arrayexpress
Project description:Autosomal dominant polycystic liver disease (ADPLD) is caused by mutations in PRKCSH, SEC63, and LRP5, while autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1, and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions using high-density SNP microarrays to find novel polycystic liver disease genes. We collected 46 cysts from 23 patients with polycystic or sporadic hepatic cysts, and analyzed DNA from those cysts using high-resolution microarray (n=24) or Sanger sequencing (n=22). We here focused on regions of homozygosity on the autosomes (>3.0Mb), and large CNVs (>1.0Mb). We found frequent LOH in PRKCSH (22/29), and PKD1/PKD2 (2/3) cysts of patients with known heterozygous germline variants in the respective genes. In the total cohort, 12/23 patients harbored abnormalities outside of familiar areas. In individual ADPLD cases, we identified germline events: a 2q13 complex rearrangement resulting in BUB1 haploinsufficiency, a 47XXX karyotype, chromosome 9q copy number loss, and LOH on chromosome 3p. The latter region was overlapping with an LOH region identified in two other cysts. Unique germline and somatic abnormalities occur frequently in and outside of known genes underlying cysts. Each liver cyst has a unique genetic makeup. LOH driver gene BUB1 may imply germline causes of genetic instability in PLD. 24 liver cysts from 23 patients
2016-06-30 | E-GEOD-78808 | biostudies-arrayexpress
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:Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple fluid-filled cysts that destroy the kidney architecture resulting in end-stage renal failure. Mutations in the ADPKD genes PKD1 and PKD2 account for nearly all the cases of ADPKD. Increased cell proliferation is one of the key features of the disease. Several studies indicated that polycystin-1, the product of PKD1, regulates cellular proliferation through various signaling pathways, but little is known about the role played by polycystin-2, the product of PKD2. Recently, it was reported that as with polycystin-1, polycystin-2 can acts as a negative regulator of cell growth by modulating the levels of the cyclin-dependent kinase inhibitor, p21 and the activity of the cyclin-dependent kinase 2, Cdk2. In this study we utilized different kidney cell lines expressing wild-type and mutant PKD2 as well as primary tubular epithelial cells isolated from a PKD transgenic rat to further explore the contribution of the p21/Cdk2 pathway in ADPKD proliferation. Surprisingly, over-expression of wild-type PKD2 in renal cell lines failed to inactivate Cdk2 activity and consequently had no effect on cell proliferation. On the other hand, expression of mutated PKD2 augmented proliferation only in the primary tubular epithelial cells of a rat model but this was independent of STAT-1/p21 pathway. Genome-wide expression analysis in these cells revealed that expression of the cyclin-dependent kinase inhibitor, p57 is downregulated, while p21 remains unchanged. This p57 reduction is accompanied by an increase in Cdk2 levels. Our results indicate the probable involvement of p57 on epithelial cell proliferation in polycystic kidney disease. In addition, it confirms that PKD2-induced proliferation is a multifactorial process. We used microarrays to study the modulation of gene expression by mutated PKD2 in the primary tubular epithelial cells of a transgenic rat mode Keywords: transgene Gene expression in the primary tubular epithelial of a transgenic rat mode with mutated PKD2 was compared with that of SD control rats
2010-05-19 | E-GEOD-11500 | biostudies-arrayexpress
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