Hepatocyte nuclear factor-1β regulates Wnt signaling through genome-wide competition with β-catenin/lymphoid enhancer binding factor
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ABSTRACT:
PROVIDER: PRJNA534126 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8943450_1.fastq.gz | Fastqsanger.gz | |||
| SRR8943450_2.fastq.gz | Fastqsanger.gz | |||
| SRR8943460_1.fastq.gz | Fastqsanger.gz | |||
| SRR8943460_2.fastq.gz | Fastqsanger.gz | |||
| SRR8943470.fastq.gz | Fastqsanger.gz |
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Project description:Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is essential for normal kidney development and renal tubular function. Mutations of HNF-1β produce cystic kidney disease, a phenotype associated with deregulation of canonical (β-catenin-dependent) Wnt signaling. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells produces hyperresponsiveness to Wnt ligands and increases expression of Wnt target genes, including Axin2, Ccdc80, and Rnf43. Levels of β-catenin and expression of Wnt target genes are also increased in HNF-1β mutant mouse kidneys. Genome-wide ChIP-seq in wild-type and mutant cells showed that ablation of HNF-1β increases by five-fold the number of sites on chromatin that are occupied by β-catenin. Remarkably, 50% of the sites that are occupied by β-catenin in HNF-1β mutant cells colocalize with HNF-1β binding sites in wild-type cells, indicating widespread reciprocal binding. We found that the Wnt target genes Ccdc80 and Rnf43 contain a novel composite DNA element comprising a β-catenin/lymphoid enhancer binding factor (LEF) site overlapping with an HNF-1β half-site. HNF-1β directly competes with the binding of β-catenin/LEF complexes to this element and thereby inhibits β-catenin-dependent transcription. Collectively, these studies reveal a novel mechanism whereby a transcription factor constrains canonical Wnt signaling through direct inhibition of β-catenin/LEF chromatin binding.
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Project description:Hepatocyte nuclear factor-1? (HNF-1?) is a tissue-specific transcription factor that is essential for normal kidney development and renal tubular function. Mutations of HNF-1? produce cystic kidney disease, a phenotype associated with deregulation of canonical (?-catenin-dependent) Wnt signaling. Here, we show that ablation of HNF-1? in mIMCD3 renal epithelial cells produces hyperresponsiveness to Wnt ligands and increases expression of Wnt target genes, including Axin2, Ccdc80, and Rnf43 Levels of ?-catenin and expression of Wnt target genes are also increased in HNF-1? mutant mouse kidneys. Genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) in wild-type and mutant cells showed that ablation of HNF-1? increases by 6-fold the number of sites on chromatin that are occupied by ?-catenin. Remarkably, 50% of the sites that are occupied by ?-catenin in HNF-1? mutant cells colocalize with HNF-1?-occupied sites in wild-type cells, indicating widespread reciprocal binding. We found that the Wnt target genes Ccdc80 and Rnf43 contain a composite DNA element comprising a ?-catenin/lymphoid enhancer binding factor (LEF) site overlapping with an HNF-1? half-site. HNF-1? and ?-catenin/LEF compete for binding to this element, and thereby HNF-1? inhibits ?-catenin-dependent transcription. Collectively, these studies reveal a mechanism whereby a transcription factor constrains canonical Wnt signaling through direct inhibition of ?-catenin/LEF chromatin binding.
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Project description:Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is essential for the development of the kidney. Mutations of HNF-1β produce autosomal dominant tubulointerstitial kidney disease (ADTKD) characterized by tubular cysts, renal fibrosis, and progressive decline in kidney function. To understand the functions of HNF-1β, we generated HNF-1β-deficient mIMCD3 renal epithelial cells. Gene editing with CRISPR/Cas9 was used to delete exon 1 of HNF-1β by non-homologous end joining (NHEJ). We performed RNA-seq on three independent HNF-1β-deficient mIMCD3 cell lines and three paired control cell lines. Our RNA-seq of HNF-1β-deficient cells showed upregulation of 1,135 genes and repression of 759 genes compared to control cells. Pathway analysis revealed that fibrosis and epithelial-mesenchymal transition (EMT) pathways were highly activated in HNF-1β-deficient cells. We conclude that loss of HNF-1β in renal epithelial cells leads to the activation of a transcriptional network that induces EMT and aberrant TGFβ signaling. Targeting this network may inhibit fibrosis in ADTKD and other chronic kidney diseases.
2018-08-10 | GSE97770 | GEO
Project description:Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is required for normal kidney development and renal epithelial differentiation. Mutations of HNF-1β produce congenital kidney abnormalities and inherited renal tubulopathies. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells results in activation of β-catenin and increased expression of lymphoid enhancer-binding factor 1 (LEF1), a downstream effector in the canonical Wnt signaling pathway. Increased expression and nuclear localization of LEF1 are also observed in cystic kidneys from Hnf1b mutant mice. Expression of dominant-negative mutant HNF-1β in mIMCD3 cells produces hyperresponsiveness to exogenous Wnt ligands, which is inhibited by siRNA-mediated knockdown of Lef1. WT HNF-1β binds to two evolutionarily conserved sites located 94 and 30 kb from the mouse Lef1 promoter. Ablation of HNF-1β decreases H3K27 trimethylation repressive marks and increases β-catenin occupancy at a site 4 kb upstream to Lef1. Mechanistically, WT HNF-1β recruits the polycomb-repressive complex 2 that catalyzes H3K27 trimethylation. Deletion of the β-catenin-binding domain of LEF1 in HNF-1β-deficient cells abolishes the increase in Lef1 transcription and decreases the expression of downstream Wnt target genes. The canonical Wnt target gene, Axin2, is also a direct transcriptional target of HNF-1β through binding to negative regulatory elements in the gene promoter. These findings demonstrate that HNF-1β regulates canonical Wnt target genes through long-range effects on histone methylation at Wnt enhancers and reveal a new mode of active transcriptional repression by HNF-1β.
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Project description:Cultured Madin-Darby canine kidney (MDCK) cells treated with hepatocyte growth factor (HGF) for 0, 3 and 24 hours. Each time point in triplicate. Keywords: time-course
2003-11-04 | GSE578 | GEO
Project description:HNF-1β is a tissue-specific transcription factor that is expressed in the kidney and other epithelial organs. Humans with mutations in HNF-1β develop kidney cysts, and HNF-1β regulates the transcription of several cystic disease genes. However, the complete spectrum of HNF-1β-regulated genes and pathways is not known. Here, using chromatin immunoprecipitation/next generation sequencing and gene expression profiling, we identified 1545 protein-coding genes that are directly regulated by HNF-1β in murine kidney epithelial cells. Pathway analysis predicted that HNF-1β regulates cholesterol metabolism. Expression of dominant negative mutant HNF-1β or kidney-specific inactivation of HNF-1β decreased the expression of genes that are essential for cholesterol synthesis, including sterol regulatory element binding factor 2 (Srebf2) and 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr). HNF-1β mutant cells also expressed lower levels of cholesterol biosynthetic intermediates and had a lower rate of cholesterol synthesis than control cells. Additionally, depletion of cholesterol in the culture medium mitigated the inhibitory effects of mutant HNF-1β on the proteins encoded by Srebf2 and Hmgcr, and HNF-1β directly controlled the renal epithelial expression of proprotein convertase subtilisin-like kexin type 9, a key regulator of cholesterol uptake. These findings reveal a novel role of HNF-1β in a transcriptional network that regulates intrarenal cholesterol metabolism.
| S-EPMC4978044 | biostudies-literature
Project description:Hepatocyte nuclear factor-1β (HNF-1β) is an essential transcription factor that regulates tissue-specific gene expression in the kidney, liver, pancreas and genitourinary tract. In humans, mutations of HNF-1β cause renal cysts and diabetes (RCAD) and congenital anomalies of the kidney and urinary tract (CAKUT). Inactivation of Hnf-1β in tubular epithelial cells throughout the nephron leads to early-onset cyst formation and postnatal lethality. Here, we used Pkhd1/Cre mice to delete Hnf-1β specifically in renal collecting ducts (CD). Hnf-1β mutant mice survived long-term and developed slowly progressive cystic kidney disease, renal fibrosis, and hydronephrosis. Compared with wild-type littermates, Hnf-1β mutant mice had higher urine volume, lower urine osmolality, and higher water intake. Differences were seen at baseline, following 24h water restriction, and following administration of dDAVP. Circulating ADH levels were similar in wild type and mutant mice. Polyuria, polydipsia, and decreased urine osmolality were present prior to the onset of cyst formation and hydronephrosis. These findings indicated that Hnf-1β mutant mice have a primary defect in urinary concentrating ability. Studies using in vitro hypertonicity response experiments identified NR1H4 (FXR), a transcription factor previously shown to regulate water homeostasis, as a novel HNF-1β target. mIMCD3 cells exposed to hypertonic medium robustly upregulated Fxr mRNA levels; this upregulation was lost in Hnf-1β mutant cells. HNF-1β was bound to the Fxr promoter region in vivo, and Fxr mRNA was significantly downregulated in mutant mice. FXR protein localized to CD in wild-type mice and was almost undetectable in the cyst epithelium of mutant mice. These findings highlight a new and critical role for HNF-1β in urinary concentration and hypertonicity by regulating the transcription of FXR in the CD.
2017-06-13 | GSE85976 | GEO
Project description:Genome Wide mapping of Hnf-1β in kidney cells. Tissue-specific transcription factor that is expressed in the kidney and other epithelial organs. Humans with mutations in HNF1? develop kidney cysts, and HNF-1β regulates the transcription of several cystic disease genes. However, the complete spectrum of HNF-1β-regulated genes and pathways is not known. Here, we used ChIP-seq and DNA microarray analysis to identify 1,545 protein-coding genes that are directly regulated by HNF-1β in kidney epithelial cells. Pathway analysis predicted that HNF-1β regulates cholesterol metabolism. The expression of genes that are essential for cholesterol synthesis, including Srebf2 and Hmgcr, was reduced by expression of dominant-negative mutant HNF-1β or kidney-specific inactivation of HNF-1β. The levels of cholesterol biosynthetic intermediates and the rate of cholesterol synthesis were decreased in HNF-1β mutant cells. In addition, HNF-1β directly regulated the renal epithelial expression of PCSK9, a key regulator of cholesterol uptake, and depletion of cholesterol in the culture medium mitigated the inhibitory effects of mutant HNF-1β on SREBP-2 and HMGCR. These findings reveal a novel role of HNF-1β in regulating multiple steps in renal cholesterol metabolism.
2015-08-15 | GSE71250 | GEO