Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA290705 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2124924.fastq.gz | Fastqsanger.gz | |||
| SRR2124925.fastq.gz | Fastqsanger.gz | |||
| SRR2124926.fastq.gz | Fastqsanger.gz | |||
| SRR2124927.fastq.gz | Fastqsanger.gz |
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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
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:HNF-1β mutations are one of the most common single-gene mutations that underlie kidney developmental disease. Hepatocyte nuclear factor 1β (HNF-1β) is essential for kidney development, but its functions in kidney development are incompletely understood. We identified 8284 HNF-1β binding sites using ChIP-sequencing. The majority of these peaks map to promoter (26%), intron (34%) or distal intergenic regions (37.4%) of the mouse genome. 61% of peaks map to protein coding genes, 12% map to long-noncoding RNAs, and 2% map to miRNAs.
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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:HNF-1β mutations are one of the most common single-gene mutations that underlie kidney developmental disease. Hepatocyte nuclear factor 1β (HNF-1β) is essential for kidney development, but its functions in ureteric bud (UB) branching morphogenesis are incompletely understood. We isolated E14.5 UB cells using fluorescence-activated cell sorting, and performed RNA-sequencing to compare gene expression in wild-type and HNF-1β deficient UB cells. 1632 genes have significantly lower expression in the HNF-1β deficient UB cells and 2223 genes have significantly higher expression in HNF-1β deficient UB cells.
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