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FXR isoform selective DNA binding in mouse liver organoids

ABSTRACT: FXR isoform selective DNA binding in mouse liver organoids

PROVIDER: PRJNA552280 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9626980.fastq.gz	Fastqsanger.gz
	SRR9626990.fastq.gz	Fastqsanger.gz
	SRR9627000.fastq.gz	Fastqsanger.gz
	SRR9627010.fastq.gz	Fastqsanger.gz
	SRR9626981.fastq.gz	Fastqsanger.gz

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FXR isoform selective DNA binding in mouse liver organoids

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

FXR isoform selective transcriptional activation in mouse liver organoids

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.

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FXR isoform selective transcriptional activation in mouse liver organoids

Project description:FXR isoform selective transcriptional activation in mouse liver organoids

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FXR isoform selective effects on hepatoma cell line HepG2

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.

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FXR isoform selective effects on hepatoma cell line HepG2

Project description:FXR isoform selective effects on hepatoma cell line HepG2

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FXR and RXRA binding in mouse liver

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.

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FXR and RXRA binding in mouse liver

Project description:FXR and RXRA binding in mouse liver

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FXR controls gene expression independently of RXR at non-canonical response elements

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.

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FXR cistrome in mouse liver

Project description:FXR ChIP-seq was performed using the liver from adult male C57Bl6 mice

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Development of gene expression signatures in the liver cancer cells with FXR overexpression and FXR activation

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