title: ChIPing the cistrome of PXR in mouse liver.
abstract: The pregnane X receptor (PXR) is a key regulator of xenobiotic metabolism and disposition in liver. However, little is known about the PXR DNA-binding signatures in vivo, or how PXR regulates novel direct targets on a genome-wide scale. Therefore, we generated a roadmap of hepatic PXR bindings in the entire mouse genome [chromatin immunoprecipitation (ChIP)-Seq]. The most frequent PXR DNA-binding motif is the AGTTCA-like direct repeat with a 4 bp spacer [direct repeat (DR)-4)]. Surprisingly, there are also high motif occurrences with spacers of a periodicity of 5 bp, forming a novel DR-(5 n+4) pattern for PXR binding. PXR-binding overlaps with the epigenetic mark for gene activation (histone-H3K4-di-methylation), but not with epigenetic marks for gene suppression (DNA methylation or histone-H3K27-tri-methylation) (ChIP-on-chip). After administering a PXR agonist, changes in mRNA of most PXR-direct target genes correlate with increased PXR binding. Specifically, increased PXR binding triggers the trans-activation of critical drug-metabolizing enzymes and transporters. The mRNA induction of these genes is absent in PXR-null mice. The current work provides the first in vivo evidence of PXR DNA-binding signatures in the mouse genome, paving the path for predicting and further understanding the multifaceted roles of PXR in liver.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Julia Yue
authors.initials: JY
authors.lastname: Cui
authors.forename: Sumedha S
authors.initials: SS
authors.lastname: Gunewardena
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Rockwell
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D000818:Animals; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D016678:Genome; D008658:Inactivation, Metabolic / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000096:biosynthesis; D011987:Receptors, Steroid / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid; D020218:Response Elements; D017422:Sequence Analysis, DNA
chemical_list: D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D004247:DNA