Development of gene expression signatures in the liver cancer cells with FXR overexpression and FXR activation
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PROVIDER: PRJNA627404 | ENA |
REPOSITORIES: ENA
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Project description:To investigate the role of nuclear receptor FXR during hepatocarcinogenesis, HepG2 cels and SK-Hep-1 cells were transfected with lentiviral mediated FXR overexpressive vector or the negative control. After the cells were treated with FXR agonist GW4064 2uM for 24 h, and total RNA were isolated for detection of gene expression .
2020-09-10 | GSE149111 | GEO
Project description:The farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids that regulates metabolic processes. FXR is expressed as four isoforms (α1-4), and their relative abundance is specific to tissue and bio-energetic conditions (Correia JC et al. 2015). Depending on the FXR isoform expressed, there is a degree of selectivity in target-genes activation. In this dataset, we defined FXR-isoforms selective effects on transcription in mouse liver organoids after treatment with the FXR agonist Obeticholic acid(OCA). By linking the DNA binding profiles of the FXR isoforms with their transcriptional output, we concluded that differential DNA binding plays a defining role in FXR-isoform target gene selectivity.
2020-07-27 | GSE133734 | GEO
Project description:The Farnesoid-X-Receptor (FXR) is a nuclear receptor (NR) known to obligately heterodimerize with Retinoid-X-Receptor (RXR). FXR is expressed as four isoforms (α1-α4) that drive transcription from IR-1 (inverted repeat-1) DNA motifs. More recently, FXR isoforms α2/α4 were found to activate transcription predominantly from non-canonical ER-2 (everted repeat-2) DNA motifs, mediating most metabolic effects of general FXR activation.Here, we explored whether co-occupancy of FXR and RXR in the mouse liver has an influence on DNA motif binding preference. We found RXR acts as a molecular switch, promoting FXRα2 activation from IR-1 instead of ER-2 motifs. Our results showcase FXR as the first NR with RXR-dependent and independent modes of activation, highlighting a potential new layer of complexity for other RXR-heterodimerizing NRs.
2024-03-20 | GSE261901 | GEO
Project description:Cancer-associated fibroblasts (CAFs), the principal components of tumor microenvironment, play multiple roles in breast cancer onset and progression. While their impact is widely accepted, treatment options to target CAFs in clinical practice were not yet well established. The nuclear receptor superfamily encompasses a druggable class of molecules, expressed in various stroma and parenchymal cell types, with the interesting therapeutic potential to modulate the reactive microenvironment. Having already addressed the oncosuppressive role of the nuclear Farnesoid X Receptor (FXR) in mammary epithelial cancer cells, the present study is aimed to assess the function of FXR in CAFs and evaluate whether its activation may affect their tumor-promoting features.
2018-12-31 | E-MTAB-6343 | biostudies-arrayexpress
Project description:FXR isoform selective transcriptional activation in mouse liver organoids
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Project description:The Farnesoid-X-Receptor (FXR) is a class II nuclear receptor (NR), a class that obligately heterodimerizes with the Retinoid-X-Receptor (RXR). FXR is expressed as 4 isoforms (α1-α4) activated by bile acids that drive transcription from response elements IR-1 (inverted repeat-1). We recently showed that FXR isoforms α2 and α4 bind to non-canonical response elements ER-2 (everted repeat-2), thereby increasing mitochondrial respiratory capacity and limiting de novo lipogenesis. Binding to ER-2 motifs in mouse liver organoids represented 89% of all FXR genome wide binding. However, mechanistic differences in FXR binding and activation from these two response elements remained unexplored. Using DNA pull down followed by mass-spectrometry, we show that RXR is not involved in FXR binding to ER-2 response elements. Instead, RXR inhibited FXR binding and activation from these elements in luciferase reporters. Genome wide, RXR-lacking FXR binding sites showed higher enrichment for ER-2 motifs in mouse liver. Pharmacological and mutational abrogation of FXR-RXR heterodimerization specifically retained ER-2 transactivation capacities in luciferase reporters and HepG2 cells. Transcriptome-wide, 25% of FXR targets were inhibited upon RXR overexpression, but specifically activated by a novel heterodimerization-deficient mutant FXRα2L434R. These genes were ER-2 responsive and were involved in lipid metabolism and ammonia detoxification. In conclusion, we discovered that RXR is not required and even inhibits binding of FXRα2 to ER-2. Thus, whereas FXR α1 and α3 seem to be genuine class II NR, FXRα2 and α4 are facultative class II at ER-2 motifs. This novel feature holds promise to exploit and tailor therapeutic responses to FXR agonism.
2024-11-12 | PXD047930 | Pride
Project description:Aging and unhealthy diets are risks for metabolic diseases including liver cancer. Bile acid receptor farnesoid X receptor (FXR) knockout (KO) mice develop metabolic liver diseases and progress into liver cancer as they age, and Western diet (WD) intake facilitates liver carcinogenesis in those mice. This study aimed to uncover molecular signatures within the gut-liver axis for diet and age-linked liver diseases in FXR-dependent or independent manners. Many more transcripts were changed due to WD intake and aging in WT mice than those in FXR KO mice. In other words, WD intake and aging impact the hepatic transcriptomes and metabolomes in an FXR-dependent manner. In WT mice, WD/aging upregulated inflammation-related genes and downregulated genes involved in oxidative phosphorylation (OXPHOS). Urine metabolomes provided clear distinguishing for differential dietary intake. By contrast, the metabolomes of the liver, serum, or urine could reflect age differences. Further, irrespective of differential diets intake or ages, transcriptomes, metabolomes, and cecal microbiota distinguished WT and FXR KO. Western dietary patterns and aging share molecular commonality with FXR deactivation. Notably, WD, aging, and FXR deactivation commonly altered hepatic cell division-related transcripts (Cenpe, Ect2, Top2a, Kif20a, Tpx2, Nuf2, Kif18b, Aspm, E2f8, and Hmmr), which are associated with overall survival rate in HCC patients. In conclusion, FXR is essential for maintaining metabolic homeostasis in response to WD intake and aging. FXR activation helps to alleviate diet and/or aging-induced metabolic health issues.
2023-02-22 | GSE216375 | GEO
Project description:The farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids that regulates metabolic processes. FXR is expressed as four isoforms (α1-4), and their relative abundance is specific to tissue and bio-energetic conditions (Correia JC et al. 2015). Depending on the FXR isoform expressed, there is a degree of selectivity in target-genes activation. However, there is currently no data on how isoform-linked target selectivity is achieved. In this study we investigate the DNA binding profile of FXR isoforms on mouse liver organoids treated briefly with the FXR agonist obeticholic acid (OCA). From this analysis we concluded that FXR isoforms α2 and α4 binds to additional DNA regions, enriched for a specific discriminating binding motif. This binding led to isoform-selective gene regulation. Therefore, DNA binding selectivity therefore plays a defining role in FXR isoform-specific effects.
2020-07-27 | GSE133700 | GEO
Project description:FXR activation inhibits CAF tumor-promoting features
| PRJEB24405 | ENA
Project description:Bile acid (BA) homeostasis is maintained through a feedback loop operated by the nuclear hormone receptors FXR and SHP. Here we show that contrary to the current models placing FXR upstream of SHP in a linear regulatory pathway, the phenotypic consequence of the combined loss of both receptors is much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. This is highlighted by the dramatic elevation of hepatic and serum BA levels in the double knockout (DKO) mice as early as three weeks of age coupled with a commensurate increase in Cyp7A1 expression and alterations in BA homeostatic genes. In addition, we find several genes necessary for C21 steroid biosynthetic pathway as novel targets for FXR and SHP. The elevated BAs result in severe hepato-pathology but the DKO mice surprisingly do not develop complete liver failure and live for over a year. Their survival is accompanied by an adaptive proliferation of the resident liver progenitor cell population, known as oval cells. Overall, these data demonstrate that FXR and SHP function coordinately to maintain BA homeostasis, and identify DKO mice as a novel genetic model for juvenile cholestatic disorders and for oval cell activation. Liver samples collected from FXR-/-, SHP-/-, and FXR-/-/SHP-/- animals at 3 or 5 weeks were hybridized to Illumina mouse REF-8 v1.1 arrays in duplicate.
2010-12-10 | E-GEOD-20599 | biostudies-arrayexpress