Hepatocyte nuclear factor 1β binding in E14.5 kidney
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE205189 | GEO | 2022/10/20
REPOSITORIES: GEO
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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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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.
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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.
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Project description:Analysis of metabolic pathway gene expression. The hypothesis tested in the present study is to assess mRNA level changes in metabolic genes in enterocytes from intestine specific PGC-1β konckout mice. Total RNA obtained from ileum samples from IKOPGC-1β mice was compared to the total RNA extracted from their wild-type littermates.
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