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Hepatocyte nuclear factor-1β regulates Wnt signaling through genome-wide competition with β-catenin/lymphoid enhancer binding factor

ABSTRACT: Hepatocyte nuclear factor-1β regulates Wnt signaling through genome-wide competition with β-catenin/lymphoid enhancer binding factor

PROVIDER: PRJNA534126 | ENA |

REPOSITORIES: ENA

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			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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Hepatocyte nuclear factor-1β regulates Wnt signaling through genome-wide competition with β-catenin/lymphoid enhancer binding factor

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.

2019-11-11 | GSE130164 | GEO

Hepatocyte nuclear factor 1β binding in E14.5 kidney

Project description:Hepatocyte nuclear factor 1β binding in E14.5 kidney

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Hepatocyte nuclear factor 1β binding in E14.5 kidney

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.

2022-10-20 | GSE205189 | GEO

Hepatocyte nuclear factor 1β gene regulation in E14.5 ureteric bud cells

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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Hepatocyte nuclear factor 1β gene regulation in E14.5 ureteric bud cells

Project description:Hepatocyte nuclear factor 1β gene regulation in E14.5 ureteric bud cells

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Transcription factor hepatocyte nuclear factor 1β controls a transcriptional network regulating cell polarity in kidney cells

Project description:Transcription factor hepatocyte nuclear factor 1β controls a transcriptional network regulating cell polarity in kidney cells

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Hepatocyte nuclear factor-1? regulates Wnt signaling through genome-wide competition with ?-catenin/lymphoid enhancer binding factor.

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.

| S-EPMC6883834 | biostudies-literature

Transcription factor cooperation and competition

Project description:Transcription factor cooperation and competition

| PRJNA933216 | ENA

Inactivation of transcription factor HNF-1β with CRISPR/Cas9 induces epithelial-mesenchymal transition

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

Hepatocyte nuclear factor 1β suppresses canonical Wnt signaling through transcriptional repression of lymphoid enhancer-binding factor 1.

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.

| S-EPMC7762946 | biostudies-literature

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