Dual β-catenin and γ-catenin loss in hepatocytes impacts their polarity through altered TGFβ and HNF4⍺ signaling
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PROVIDER: PRJNA699243 | ENA |
REPOSITORIES: ENA
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Project description:Hepatocytes are highly polarized epithelia. Loss of hepatocyte polarity is associated with various liver diseases, including cholestasis. However, the molecular underpinnings of hepatocyte polarization remain poorly understood. Previously, we have shown that loss of β-catenin at adherens junctions (AJs) is compensated by β-catenin and dual loss of both catenins in dual knockouts (DKO) in mice liver leads to progressive intrahepatic cholestasis. However, the clinical relevance of this observation, and further phenotypic characterization of the phenotype, is important. Here, we identify simultaneous loss of β- and γ-catenin in a subset of liver samples from patients of progressive familial intrahepatic cholestasis and primary sclerosing cholangitis. Hepatocytes in DKO mice exhibited defect in apical-basolateral localization of polarity proteins, impaired bile canaliculi formation, and loss of microvilli. Loss of polarity in DKO livers manifested as epithelial-to-mesenchymal transition, increased hepatocyte proliferation, and suppression of hepatocyte differentiation, which was associated with up-regulation of TGFβ signaling and repression of Hnf4α expression and activity. In conclusion, concomitant loss of the two catenins in the liver may be playing a pathogenic role in subsets of cholangiopathies. Our findings also support a previously unknown role β- and γ-catenin in the maintenance of hepatocyte polarity. Improved understanding of the regulation of hepatocyte polarization processes by β and γ-catenin could potentially benefit development of new therapies for cholestasis.
2021-02-14 | GSE166087 | GEO
Project description:To define changes in gene expression resulting from loss of hnf4 in the small intestine. Keywords: genetic modification
2005-12-31 | GSE3124 | GEO
Project description:HNF4 paralogs are redundantly required for proper villus elongation, differentiation and maturation in the developing gut. We find 5,391 chromatin regions become inaccessible upon HNF4 loss, and HNF4 binding sequences are most enriched in these regions. Genes nearby these 5,391 HNF4 dependent regions are associated with villus differentiation/maturation.
2019-07-29 | GSE128674 | GEO
Project description:Background and Aims: HNF4? is a nuclear hormone receptor transcription factor that has been shown to be required for hepatocyte differentiation and development of the liver. It has also been implicated in regulating expression of genes that act in the epithelium of the lower gastrointestinal tract. This implied that HNF4? might be required for development of the gut. Methods: We generated mouse embryos in which Hnf4? was ablated in the epithelial cells of the fetal colon using Cre-loxP technology. Embryos were examined using a combination of histology, immunohistochemistry, gene array and RT-PCR, and chromatin immunoprecipitation analyses to define the consequence of loss of HNF4? on colon development. Results: Embryos could be generated until E18.5 that lacked HNF4? in their colon. Although, early stages of colonic development occurred, HNF4? null colons failed to form normal crypts. In addition, goblet cell maturation was perturbed and expression of an array of genes that encode proteins with diverse roles in colon function was disrupted. Several genes whose expression in the colon was dependent on HNF4? contained HNF4?âbinding sites sequences within putative transcriptional regulatory regions and a subset of these sites were occupied by HNF4? in vivo. Conclusion: HNF4? is a transcription factor that is essential for development of the mammalian colon, regulates goblet cell maturation and is required for expression of genes that control normal colon function and epithelial cell differentiation. Experiment Overall Design: COMPARISON OF 3 MUTANT TO 2 CONTROL COLONS.
2008-06-12 | E-GEOD-3116 | biostudies-arrayexpress
Project description:To define changes in gene expression resulting from loss of hnf4 in the small intestine. Experiment Overall Design: hnf4 null intestines were generated by breeding hnf4loxp mice to vill-cre mice. Animals appeared to be healthy. Gene arrays were performed on two null and two control intestines.
2008-06-12 | E-GEOD-3124 | biostudies-arrayexpress
Project description:Wnt/β-catenin signaling is important in skeletal related-tissue development. We have found that Wnt/β-catenin antagonist XAV could replace traditionally used TGFβ3 as chondrogenic inducer. Here we applied gene expression array to characterize transcriptomic changes between XAV- and TGFβ-induced chondrogenic differentiation in human bone marrow (BM) and induced pluripotent stem cell (iPSC) derived MSCs.
2023-01-04 | GSE211559 | GEO
Project description:Hepatocyte-nuclear-factor-4? (??Hnf4?) is a transcription factor that controls epithelial cell polarity and maturation during embryogenesis. Hnf4? conditional deletion during post-natal development results in minor consequences on intestinal epithelium integrity but promotes activation of the Wnt/?-catenin pathway. Here we show that Hnf4? does not act as a tumor suppressor gene but is crucial to promote gut tumorigenesis in mice. Polyp multiplicity in ApcMin mice that lacks Hnf4? is suppressed in comparison to littermate ApcMin controls. Analysis of microarray gene expression profiles from mice lacking Hnf4? in the intestinal epithelium identifies its novel function in regulating the expression of reactive oxygen species (ROS) detoxifying genes. This role is supported with the demonstration that HNF4? is functionally involved in the protection against spontaneous and 5-fluorouracil chemotherapy-induced production of intracellular ROS in colorectal cancer cell lines. The analysis of a colorectal cancer patient cohort establishes that HNF4? is significantly up-regulated at both gene transcript and protein levels in tumors relative to adjacent benign epithelial resections. Several genes involved in ROS neutralization are also up-regulated in correlation with HNF4? expression. All together, the findings point to the nuclear receptor HNF4? as a potential therapeutic target to eradicate aberrant epithelial cell resistance to ROS production during intestinal tumorigenesis. HNF4alpha was conditionally knockout in the mouse epithelial intestine with the 12.4-kb VillinCRE. A total of 3 control and 3 mutant littermates individuals were sacrificed at 7 months of age. The distal jejunum was harvested and Total RNA was isolated from each individuals. Each RNA sample was independently used to generate probes to screen affymetrix chips.
2011-01-01 | E-GEOD-20968 | biostudies-arrayexpress
Project description:We show that dHNF4 null mutant larvae are sensitive to starvation. Starved mutant larvae consume glycogen normally, but retain lipids in their midgut and fat body, and have increased levels of long chain fatty acids, suggesting that they are unable to efficiently mobilize stored fat for energy. HNF4 dependent transcripts were identified under fed and starved conditions. Microarray studies indicate reduced expression of genes that control lipid catabolism and beta-oxidation. Late second instar control and HNF4 mutant larvae were collected and fed or starved for 24 hours, and then RNA was isolated for analysis. Taken together, our results support a feed-forward model for dHNF4, in which fatty acids released from triglycerides activate the receptor, inducing enzymes that drive fatty acid oxidation for energy production. Keywords: expression profiling, HNF4, mutants, Affymetrix, Drosophila 2.0, starvation, TAG, fatty acid, beta-oxidation
2009-01-24 | GSE14531 | GEO
Project description:The β-catenin mutation is frequently observed in hepatoblastoma (HB), but the underlying mechanism by which Wnt/β-catenin signaling induces HB tumor formation is unknown. We found that expression of growth regulation by estrogen in breast cancer 1 (GREB1) depends on Wnt/β-catenin signaling in HB patients. GREB1 was localized to the nucleus where it bound Smad2/3 in a competitive manner with p300 and inhibited TGFβ signaling, thereby promoting HepG2 HB cell proliferation. Forced expression of β-catenin, YAP, and c-Met induced HB-like mouse liver tumor (BYM mice), with an increase in GREB1 expression and HB markers. Depletion of GREB1 strongly suppressed marker gene expression and HB-like liver tumorigenesis, and instead enhanced TGFβ signaling in BYM mice. Furthermore, antisense oligonucleotides for GREB1 suppressed the formation of HepG2 cell-induced tumors and HB-like tumors in vivo. We propose that GREB1 is a novel target molecule of Wnt/β-catenin signaling and required for HB progression.
2019-07-18 | GSE133976 | GEO
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