title: 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.
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 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-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 peroxisome proliferator-activated receptor (PPAR) signaling pathways, and subsequent chromatin immunoprecipitation-sequencing (ChIP-seq) mapping of PPARα binding demonstrated binding of PPARα to 71 to 88% of the identified LXR-RXR binding sites. The combination of sequence analysis of shared binding regions and 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.
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Southern Denmark, Odense, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Boergesen
authors.forename: Thomas Åskov
authors.initials: TÅ
authors.lastname: Pedersen
authors.forename: Barbara
authors.initials: B
authors.lastname: Gross
authors.forename: Simon J
authors.initials: SJ
authors.lastname: van Heeringen
authors.forename: Dik
authors.initials: D
authors.lastname: Hagenbeek
authors.forename: Christian
authors.initials: C
authors.lastname: Bindesbøll
authors.forename: Sandrine
authors.initials: S
authors.lastname: Caron
authors.forename: Fanny
authors.initials: F
authors.lastname: Lalloyer
authors.forename: Knut R
authors.initials: KR
authors.lastname: Steffensen
authors.forename: Hilde I
authors.initials: HI
authors.lastname: Nebb
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Susanne
authors.initials: S
authors.lastname: Mandrup
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D020239:Receptor Cross-Talk; D047488:Retinoid X Receptors / Q000235:genetics* / Q000378:metabolism
chemical_list: D017931:DNA Primers; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D047488:Retinoid X Receptors