Genomics

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Genome-wide profiling of LXR, RXR and PPARα in mouse liver reveals extensive sharing of binding sites


ABSTRACT: The liver X receptors (LXRs) are nuclear receptors that form permissive heterodimers with retinoid X receptor (RXR) and are important regulators of lipid metabolism in the liver. We have recently shown that RXR agonist-induced hypertriglyceridemia and hepatic steatosis in mice is dependent on LXR and correlates with an LXR-dependent hepatic induction of lipogenic genes. To further investigate the role of RXR and LXR in the regulation of hepatic gene expression, we have mapped the ligand-regulated genome-wide binding of these factors in mouse liver. We find that the RXR agonist bexarotene primarily increases the genomic binding of RXR, whereas the LXR agonist T0901317 greatly increases both LXR and RXR binding. Functional annotation of putative direct LXR target genes revealed a significant association with classical LXR-regulated pathways as well as PPAR signaling pathways, and subsequent ChIP-seq mapping of PPARα binding demonstrated binding of PPARα to 71-88% of the identified LXR:RXR binding sites. Sequence analysis of shared binding regions combined with sequential ChIP on selected sites indicate that LXR:RXR and PPARα:RXR bind to degenerate response elements in a mutually exclusive manner. Together our findings suggest extensive and unexpected cross-talk between hepatic LXR and PPARα at the level of binding to shared genomic sites LXR, RXR, PPARalpha and RNA Polymerase II ChIP-seq on livers from female C57BL/6 wild-type and/or LXRα/β-deficient mice (13 weeks of age, n=1) treated by oral gavage once daily for 14 days with the RXR agonist bexarotene (100 mg/kg body weight [mpk], in 1% carboxymethylcellulose), the LXR agonist T0901317 (T09, 30 mpk) or vehicle alone.

ORGANISM(S): Mus musculus  

SUBMITTER: Hendrik G Stunnenberg  Christian Bindesbøll   Sandrine Caron   Michael Boergesen   Bart Staels   Hilde I Nebb   Susanne Mandrup   Barbara Gross   Jan-Åke Gustafsson   Knut R Steffensen   Fanny Lalloyer   Simon J van Heeringen   Dik Hagenbeek    

PROVIDER: E-GEOD-35262 | ArrayExpress | 2012-01-31

SECONDARY ACCESSION(S): GSE35262SRP010657PRJNA152837

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications

Genome-wide profiling of liver X receptor, retinoid X receptor, and peroxisome proliferator-activated receptor α in mouse liver reveals extensive sharing of binding sites.

Boergesen Michael M   Pedersen Thomas Åskov TÅ   Gross Barbara B   van Heeringen Simon J SJ   Hagenbeek Dik D   Bindesbøll Christian C   Caron Sandrine S   Lalloyer Fanny F   Steffensen Knut R KR   Nebb Hilde I HI   Gustafsson Jan-Åke JÅ   Stunnenberg Hendrik G HG   Staels Bart B   Mandrup Susanne S  

Molecular and cellular biology 20111212 4


The liver X receptors (LXRs) are nuclear receptors that form permissive heterodimers with retinoid X receptor (RXR) and are important regulators of lipid metabolism in the liver. We have recently shown that RXR agonist-induced hypertriglyceridemia and hepatic steatosis in mice are dependent on LXRs and correlate with an LXR-dependent hepatic induction of lipogenic genes. To further investigate the roles of RXR and LXR in the regulation of hepatic gene expression, we have mapped the ligand-regula  ...[more]

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