Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA150641 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:β-catenin signaling can be both a physiological and an oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20 to 40% of hepatocellular carcinomas with specific metabolic features. We decipher the molecular determinants of β-catenin-dependent zonal transcription using mice with β-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by Tcf4 and β-catenin, their transcriptome and their metabolome. We find that Tcf4 DNA-bindings depend on β-catenin. Tcf4/β-catenin binds Wnt-responsive elements preferentially around β-catenin-induced genes. In contrast, genes repressed by β-catenin bind Tcf4 on Hnf4-responsive elements. β-catenin, Tcf4 and Hnf4α interact, dictating β-catenin transcription which is antagonistic to that elicited by Hnf4α. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by β-catenin, partly through xenobiotic nuclear receptors. We conclude that β-catenin patterns the zonal liver together with Tcf4, Hnf4α and xenobiotic nuclear receptors. This network represses lipid metabolism, and exacerbates glutamine, drug and bile metabolism, mirroring hepatocellular carcinomas with β-catenin mutational activation. In vivo liver samples in 4 conditions: Betacat activated (WCE, Tcf4 chipseq, Betacat chipseq, mRNAseq with 2 replicates), Betacat null (WCE, Tcf4 chipseq, mRNAseq with 2 replicates), Betacat control (mRNAseq with 2 replicates), Wild type (mRNAseq with 2 replicates)
2014-01-18 | E-GEOD-35213 | biostudies-arrayexpress
Project description:β-catenin signaling can be both a physiological and an oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20 to 40% of hepatocellular carcinomas with specific metabolic features. We decipher the molecular determinants of β-catenin-dependent zonal transcription using mice with β-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by Tcf4 and β-catenin, their transcriptome and their metabolome. We find that Tcf4 DNA-bindings depend on β-catenin. Tcf4/β-catenin binds Wnt-responsive elements preferentially around β-catenin-induced genes. In contrast, genes repressed by β-catenin bind Tcf4 on Hnf4-responsive elements. β-catenin, Tcf4 and Hnf4α interact, dictating β-catenin transcription which is antagonistic to that elicited by Hnf4α. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by β-catenin, partly through xenobiotic nuclear receptors. We conclude that β-catenin patterns the zonal liver together with Tcf4, Hnf4α and xenobiotic nuclear receptors. This network represses lipid metabolism, and exacerbates glutamine, drug and bile metabolism, mirroring hepatocellular carcinomas with β-catenin mutational activation.
2014-01-18 | GSE35213 | GEO
Project description:Signaling through the Wnt/b-catenin pathway is a crucial determinant of hepatic zonal gene expression, liver development, regeneration, and tumorigenesis. The gene encoding b-catenin is called Ctnnb1. We have previously shown that liver tumour promotion mediated by the model tumour promoter phenobarbital (PB) is completely lost in mice, where Ctnnb1 has been conditionally knocked out in hepatocytes (CTNNB1KO mice; Rignall et al., Carcinogenesis 32, 52-57, 2010). In the present study, the effect of a 12 weeks PB exposure on the liver miRNA expression pattern was investigated, in order to potentially get information on the nature of the loss of promotional activity in the CTNNB1KO mice.
2018-05-11 | GSE68786 | GEO
Project description:Signaling through the Wnt/b-catenin pathway is a crucial determinant of hepatic zonal gene expression, liver development, regeneration, and tumorigenesis. The gene encoding b-catenin is called Ctnnb1. We have previously shown, that liver tumour promotion mediated by the model tumour promoter phenobarbital (PB) is completely lost in mice, where Ctnnb1 has been conditionally knocked out in hepatocytes (CTNNB1KO mice; Rignall et al., Carcinogenesis 32, 52-57, 2010). In the present study, the effect of a 12 weeks PB exposure on the liver miRNA expression pattern was investigated, in order to potentially get information on the nature of the loss of promotional activity in the CTNNB1KO mice.
2018-05-11 | GSE68779 | GEO
Project description:Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal function. Wnt/beta-catenin signaling controls metabolic zonation by activating genes in the perivenous hepatocytes, while suppressing genes in the periportal counterparts. We now demonstrate that glucagon opposes the actions of Wnt/beta-catenin signaling on gene expression and metabolic zonation pattern. The effects were more pronounced in the periportal hepatocytes where 28% of all genes were activated by glucagon and inhibited by Wnt/beta-catenin. The glucagon and Wnt/beta-catenin receptors and their signaling pathways are uniformly distributed in periportal and perivenous hepatocytes and the expression is not regulated by the opposing signal. Collectively, our results show that glucagon controls gene expression and metabolic zonation in the liver through a counter play with the Wnt/beta-catenin signaling pathway.
2018-03-01 | GSE110673 | GEO
Project description:Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal function. Wnt/beta-catenin signaling controls metabolic zonation by activating genes in the perivenous hepatocytes, while suppressing genes in the periportal counterparts. We now demonstrate that glucagon opposes the actions of Wnt/beta-catenin signaling on gene expression and metabolic zonation pattern. The effects were more pronounced in the periportal hepatocytes where 28% of all genes were activated by glucagon and inhibited by Wnt/beta-catenin. The glucagon and Wnt/beta-catenin receptors and their signaling pathways are uniformly distributed in periportal and perivenous hepatocytes and the expression is not regulated by the opposing signal. Collectively, our results show that glucagon controls gene expression and metabolic zonation in the liver through a counter play with the Wnt/beta-catenin signaling pathway.
2018-03-01 | GSE110672 | GEO
Project description:The metabolic functions of the liver are organized spatially in a phenomenon known as zonation. This spatial organization of metabolic functions is linked to the differential exposure of central and portal hepatocytes to either systemic circulation or nutrient-rich blood afferent from the gastrointestinal tract, respectively. The mechanistic target of rapamycin complex 1 (mTORC1) is the central hub of a critical signaling pathway that links cellular metabolism to fluctuations in the levels of nutrients and insulin. To understand how these two signaling cues are integrated in the liver, we have generated mice with constitutive nutrient and insulin signaling to mTORC1 in hepatocytes (RragaGTP/fl; Tsc1fl/fl; Albumin-CreTg mice). Simultaneous activation of nutrient and hormone signaling to mTORC1 results in impaired establishment of the metabolic zonal identity of hepatocytes, a maturation process that takes place within the first weeks after birth. Mechanistically, a decrease in levels of the morphogenic pathway Wnt/β-catenin in hepatocytes and reduced expression of the Wnt2 ligand by liver endothelial cells after birth underlie this impaired wave of hepatocyte maturation. Lack of postnatal establishment of metabolic zonation of the liver is recapitulated in a model of constant supply of nutrients by total parenteral nutrition to neonatal pigs. Collectively, our work shows the critical role of hepatocyte sensing of fluctuations in nutrients and hormones after birth for triggering the latent metabolic zonation program.
2024-03-18 | PXD041439 | Pride
Project description:Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent β-catenin activating mutations. Here, we demonstrate that this differentiated state is maintained by a balance between nuclear, tissue-specific β-catenin-containing complexes and the ACC epigenome. On chromatin, β-catenin binds master adrenal transcription factor SF1 and hijacks the adrenocortical super-enhancer landscape to maintain differentiation. Off chromatin, β-catenin binds histone methyltransferase EZH2, which is redistributed by the CIMP-high DNA methylation signature. SF1/β-catenin and EZH2/β-catenin complexes exist in normal adrenals and are selected for through all phases of ACC evolution. EZH2 inhibition in CIMP-high ACC favors EZH2/β-catenin assembly and purges SF1/β-catenin from chromatin, erasing differentiation and restraining cancer growth in vitro and in vivo. Our studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities.
2023-04-25 | GSE205272 | GEO
Project description:Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent β-catenin activating mutations. Here, we demonstrate that this differentiated state is maintained by a balance between nuclear, tissue-specific β-catenin-containing complexes and the ACC epigenome. On chromatin, β-catenin binds master adrenal transcription factor SF1 and hijacks the adrenocortical super-enhancer landscape to maintain differentiation. Off chromatin, β-catenin binds histone methyltransferase EZH2, which is redistributed by the CIMP-high DNA methylation signature. SF1/β-catenin and EZH2/β-catenin complexes exist in normal adrenals and are selected for through all phases of ACC evolution. EZH2 inhibition in CIMP-high ACC favors EZH2/β-catenin assembly and purges SF1/β-catenin from chromatin, erasing differentiation and restraining cancer growth in vitro and in vivo. Our studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities.
2023-04-25 | GSE205261 | GEO
Project description:Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent β-catenin activating mutations. Here, we demonstrate that this differentiated state is maintained by a balance between nuclear, tissue-specific β-catenin-containing complexes and the ACC epigenome. On chromatin, β-catenin binds master adrenal transcription factor SF1 and hijacks the adrenocortical super-enhancer landscape to maintain differentiation. Off chromatin, β-catenin binds histone methyltransferase EZH2, which is redistributed by the CIMP-high DNA methylation signature. SF1/β-catenin and EZH2/β-catenin complexes exist in normal adrenals and are selected for through all phases of ACC evolution. EZH2 inhibition in CIMP-high ACC favors EZH2/β-catenin assembly and purges SF1/β-catenin from chromatin, erasing differentiation and restraining cancer growth in vitro and in vivo. Our studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities.
2023-04-25 | GSE205258 | GEO