Intergrated expression profiling and ChIP-SEQ analyses of ChREBP-mediated glucose response network (expression data only)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE22074 | GEO | 2010/06/04
SECONDARY ACCESSION(S): PRJNA128953
REPOSITORIES: GEO
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Project description:We identified ChREBP-binding regions from the DNA of human hepatocellular targets as well as previously-known targets Total RNA from hepG2 cell line
2010-06-16 | E-GEOD-22074 | biostudies-arrayexpress
Project description:Glucose is an important regulator of pancreatic β-cell function. In addition to the acute stimulation of insulin secretion, glucose stimulates long-term adaptive changes in gene expression that can either promote or antagonize the proliferative potential and function of β-cells. The glucose-sensing transcription factor carbohydrate response element binding protein (ChREBP) has been shown to promote both β-cell proliferation and dysfunction; however, the molecular mechanisms underlying these pleiotropic effects of ChREBP and glucose are not well understood. Here, we have generated time-resolved profiles of enhancer and transcriptional activity in response to glucose in the INS-1E pancreatic β-cell line. Our data outline a biphasic response with a first wave during which metabolic genes are activated, and a second wave where cell cycle genes are induced and β-cell identity genes are repressed. We show that ChREBP directly activates first wave genes, whereas repression and activation of second wave genes by ChREBP is indirect. By integrating motif enrichment within late-regulated enhancers with expression profiles of the associated transcription factors, we identify multiple putative regulators of the second wave, including RAR-related orphan receptor (ROR) γ, which we demonstrate is a novel direct ChREBP target gene. Importantly, we show that RORγ activity is necessary for full glucose-induced proliferation of both INS-1E and primary rat β-cells. Genome-wide assesment of the transcriptional response to glucose in INS-1E β-cells using RNA- ChIP- and DNase-seq
2016-09-06 | E-GEOD-81628 | biostudies-arrayexpress
Project description:Glucose is an important regulator of pancreatic β-cell function. In addition to the acute stimulation of insulin secretion, glucose stimulates long-term adaptive changes in gene expression that can either promote or antagonize the proliferative potential and function of β-cells. The glucose-sensing transcription factor carbohydrate response element binding protein (ChREBP) has been shown to promote both β-cell proliferation and dysfunction; however, the molecular mechanisms underlying these pleiotropic effects of ChREBP and glucose are not well understood. Here, we have generated time-resolved profiles of enhancer and transcriptional activity in response to glucose in the INS-1E pancreatic β-cell line. Our data outline a biphasic response with a first wave during which metabolic genes are activated, and a second wave where cell cycle genes are induced and β-cell identity genes are repressed. We show that ChREBP directly activates first wave genes, whereas repression and activation of second wave genes by ChREBP is indirect. By integrating motif enrichment within late-regulated enhancers with expression profiles of the associated transcription factors, we identify multiple putative regulators of the second wave, including RAR-related orphan receptor (ROR) γ, which we demonstrate is a novel direct ChREBP target gene. Importantly, we show that RORγ activity is necessary for full glucose-induced proliferation of both INS-1E and primary rat β-cells.
2016-09-06 | GSE81628 | GEO
Project description:Carbohydrate Responsive Element-Binding Protein (ChREBP) is a carbohydrate sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified Hepatocyte Growth Factor Activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone Hepatocyte Growth Factor (HGF). We demonstrate that HGFAC KO mice have phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhances lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediates an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis.
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Project description:Carbohydrate Responsive Element-Binding Protein (ChREBP) is a carbohydrate sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified Hepatocyte Growth Factor Activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone Hepatocyte Growth Factor (HGF). We demonstrate that HGFAC KO mice have phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhances lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediates an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis.
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Project description:This project investigated proline hydroxylation of ChREBP. Proline hydroxylation was investigated in flag-IP enriched protein extracts from ChREBP-flag overexpressing HEK293 cells (A) and in ChREBP-IP enriched mouse liver protein (male, C57BL6/J) (B).
2020-10-19 | PXD019137 | Pride
Project description:abstract1: Glycogen storage disease type Ia (GSD Ia) is an inborn error of metabolism caused by defective glucose-6-phosphatase (G6PC) activity. GSD Ia patients exhibit severe hepatomegaly due to glycogen and triglyceride (TG) accumulation in the liver. We have previously shown that the activity of Carbohydrate Response Element Binding Protein (ChREBP), a key regulator of glycolysis and de novo lipogenesis, is increased in GSD Ia. In the current study we assessed the contribution of ChREBP to non-alcoholic fatty liver disease (NAFLD) development in a mouse model for hepatic GSD Ia. PMID : 32083759 Abstract2:Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by a defect in glucose-6-phosphatase (G6PC) activity, which induces severe hepatomegaly and increases the risk for liver cancer in patients. Hepatic GSD Ia is characterized by constitutive activation of Carbohydrate Response Element Binding Protein (ChREBP), a glucose-sensitive transcription factor that has been proposed as a pro-oncogenic molecular switch that supports tumour progression. Here we studied the contribution of ChREBP signalling on liver disease progression and tumour susceptibility in a mouse model for GSD Ia. Hepatocyte-specific G6pc knockout (L-G6pc-/-) mice were treated with AAV-shChREBP to normalize hepatic ChREBP activity. Hepatic ChREBP normalization induced dysplastic liver growth, massively increased hepatocyte size and sensitized to hepatic inflammation and liver fibrosis in GSD Ia mice. Furthermore, the nuclear levels of the oncoprotein YAP were increased and its transcriptional targets were induced in ChREBP normalized GSD Ia mice. Hepatic ChREBP normalization furthermore induced DNA damage and mitotic activity in GSD Ia mice, while chromosomal instability, cGAS-STING pathway, senescence, and hepatocyte dedifferentiation gene signatures emerged. Upon ChREBP silencing in immortalized human hepatocytes, on the other hand, the induction of YAP target gene expression was paralleled by cell cycle arrest, cell death, and reduced proliferation. In conclusion, our findings indicate that ChREBP activity limits hepatomegaly while protecting against liver disease progression and hepatocellular tumour induction in GSD Ia. These results underline the importance to establish the context-specific roles of ChREBP to define its therapeutic potential. PMID:37085901
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Project description:The GFP or ChREBP were overexpressed in the liver of C57Bl6/J mice through adenoviral gene delivery. Mice were studied in the fed state 3 weeks later. We used microarray analysis to detail the global program of gene expression underlying ChREBP overexpression and identified distinct classes of up and down regulated genes.
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Project description:The GFP or ChREBP were overexpressed in the liver of C57Bl6/J mice through adenoviral gene delivery. Mice were studied in the fed state 3 weeks later. We used microarray analysis to detail the global programme of gene expression underlying ChREBP overexpression and identified distinct classes of up and down regulated genes.
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