FXR isoform selective transcriptional activation in mouse liver organoids
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA552358 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9636730.fastq.gz | Fastqsanger.gz | |||
| SRR9636740.fastq.gz | Fastqsanger.gz | |||
| SRR9636750.fastq.gz | Fastqsanger.gz | |||
| SRR9636731.fastq.gz | Fastqsanger.gz | |||
| SRR9636741.fastq.gz | Fastqsanger.gz |
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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 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 isoform selective DNA binding in mouse liver organoids
| PRJNA552280 | ENA
Project description:The farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids that regulates bile acid metabolism, glucose and cholesterol homeostasis. FXR is expressed as four isoforms (α1-4), and their relative abundance is tissue specific. Human livers express predominantly FXR isoforms α1 and α2. From mouse studies we know that the FXR agonist obeticholic acid (OCA) regulates expression of many genes in the liver. However, there is currently no data on the effects of OCA on FXR isoform selective gene regulation. This is particularly relevant since the relative FXR isoform amounts in the liver are regulated by general bioenergetic cues (Correia JC et al. 2015). In this study we investigate the effect of variations in FXR isoforms α1 or α2 expression on HepG2 cell lines response to treatment with OCA.
2020-07-27 | GSE133659 | GEO
Project description:FXR isoform selective effects on hepatoma cell line HepG2
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Project description:The Farnesoid X Receptor (FXR) is a bile acid-activated transcription factor which is downregulated in colorectal cancer (CRC), and has been coined as a tumor suppressor in CRC based on mouse studies. FXR is expressed as multiple isoforms of which α3 and α4 are predominantly expressed in the colon. These isoforms differ in a 12-bp region in the DNA binding domain, which is included in α3 and excluded in α4, due to alternative splicing. The 12bp exclusion results in additional alternative DNA binding and transcriptional profiles in the liver. To investigate the mechanistic and isoform-dependent underpinnings of the tumor suppressive action of FXR, we used human colon organoids in which mutations in four known CRC-driver genes; AKPS, KRAS, p53 and SMAD4 (AKPS), are engineered. We first confirmed that FXR expression is nearly absent already in early-stage CRC organoids, and show that this is due to constitutive Wnt signaling activation. Strikingly, lentiviral overexpression of FXRα4, not FXRα3, reduced proliferation in AKPS organoids in a ligand-independent manner. Transcriptomics indicated that FXRα4 selectively reduced EGFR signaling. Upon ligand addition, both FXRα3 and α4 AKPS organoids changed morphology and started budding, indicative of epithelial differentiation. Gene set enrichment analyses revealed that enterocyte, Paneth and goblet cell progenitor expression patterns were significantly enriched. In addition, electron microscopy showed the appearance of microvilli and increased nuclear circularity, indicative of differentiation towards columnar epithelium, in ligand-stimulated FXRα3 and FXRα4 AKPS organoids. In conclusion, next to a ligand-dependent and isoform-independent effect on differentiation, we describe for the first time that FXR has isoform-dependent tumor-suppressive effects via inhibition of EGFR signaling.
2025-02-01 | GSE253112 | GEO
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 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: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: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